TY - JOUR
AU - Okada,, Hideho
AB - Abstract Treatment and resolution of primary and metastatic brain tumors have long presented a challenge to oncologists. In response to the dismal survival outcomes associated with conventional therapies, various immunotherapy modalities, such as checkpoint inhibitors, vaccine, cellular immunotherapy and viral immunotherapy have been actively explored over the past couple of decades. Although improved patient survival has been more frequently noted in treatment of brain metastases, little progress has been made in improving patient survival in cases of primary brain tumors, specifically glioblastoma, which is the representative primary brain tumor discussed in this review. Herein, we will first overview the findings of recent clinical studies for treatment of primary and metastatic brain tumors with immunotherapeutic interventions. The clinical efficacy of these immunotherapies will be discussed in the context of their ability or inability to overcome inherent characteristics of the tumor as well as restricted antigen presentation and its immunosuppressive microenvironment. Additionally, this review aims to briefly inform clinicians in the field of neuro-oncology on the relevant aspects of the immune system as it pertains to the central nervous system, with special focus on the differing modes of antigen presentation and tumor microenvironment of primary and metastatic brain tumors and the role these differences may play in the efficacy of immunotherapy in eradicating the tumor. brain tumor, glioma, glioblastoma, brain metastasis, immunotherapy, immune checkpoint inhibitor, vaccine, cellular immunotherapy, viral immunotherapy, central nervous system, antigen presentation, tumor microenvironment Introduction Brain tumors can arise in any tissue of the central nervous system (CNS). These include both primary and secondary brain tumors, as well as malignant and non-malignant tumors. The incidence of all primary brain tumors is reported to be ~4–8 cases per 100 000 individuals annually, and estimated to be ~250 000 cases globally (1). Diffuse gliomas, including the most aggressive form, glioblastoma (GBM), are the most common primary malignant CNS tumors, accounting for 25.5% of all primary brain tumors and 80.8% of all primary malignant tumors (2). They typically grow invasively, progress to higher grades and most patients eventually succumb to the disease (3). Moreover, gliomas can arise in all age groups. In children, ages 0 to 19 years old, they are especially devastating and indeed the leading cause of cancer-related mortality and morbidity (4). The prognosis for children with diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), is markedly poor (5,6). As such, development of novel and effective treatment modalities is urgently warranted in both adult and pediatric glioma patients. On the other hand, secondary brain tumors, or brain metastases (BMs), are 10 times more common than primary brain tumors (7). Lung and breast cancers, as well as melanoma, are the principal primary diseases responsible for more than three-quarters of BMs (8,9). It is reported that 25–50% of all cancer patients develop BMs in their lifetime (10–12). Although primary disease can be controlled with improved therapeutics, BMs remain major obstacles that must be overcome with better treatment options to improve patient outcomes (13). Immunotherapy still holds promise both in primary and secondary brain tumors. Although the CNS was long considered as ‘immune-privileged’, the concept has been revisited recently, with the discovery of a functional lymphatic vasculature (14,15). Of note, several clinical studies have reported excellent disease control in BMs treated with immune checkpoint inhibitors (ICIs) (16–18), while no phase III trials have succeeded in confirming a robust clinical benefit for gliomas thus far (19,20). In this review, we first overview the recent preclinical/clinical advancement in immunotherapy for glioma, followed by those for BMs. As there are many excellent review articles addressing the advancements and challenges of immunotherapy for gliomas over the past several decades (21–28), here we focus primarily on specific topics, studies and articles reported in the last few years to share up-to-date insights, including therapeutic strategies with paradigm-shifting potential. Thereafter, we outline several unique components of CNS immunology crucial to understanding the similarities and differences in efficacy of immunotherapy between primary and secondary brain tumors. Recent advances for glioma The following section reviews recent studies investigating ICIs, vaccines, cellular immunotherapy, and viral immunotherapy for glioma. In particular, some intriguing therapeutic concepts have been emerging in various research areas, such as neoadjuvant ICI therapy, multiple peptide vaccines incorporating private neoantigens, chimeric antigen receptor (CAR)-T-cell therapy for novel targets, as well as various types of viral immunotherapy. ICIs for gliomas ICI therapy works by blocking inhibitory receptor–ligand interactions on immune cells, taking the brakes off the T-cells and freeing them to kill the malignancy. ICIs, especially those targeting the CTLA-4 and PD-1/PD-L1 axis, have shown dramatic and prolonged efficacy in many types of tumors, such as melanoma, lung and microsatellite instability-high colon cancers (29–33), but not for gliomas thus far. One explanation is thought to be the presence of the blood–brain barrier (BBB), as compounds > 400–600 Da cannot penetrate the BBB, such as nivolumab, an anti-PD-1 monoclonal antibody (mAb), with a molecular mass of 146 kDa (34,35). However, even though the integrity of the BBB is disrupted in tumor vasculature (36), there is evidence that antibody-mediated blockade of the PD-1/PD-L1 axis and consequent T-cell activation occurs outside of the CNS (37). Multiple preclinical and early phase clinical trials have demonstrated that tumor-specific effector T-cells bound to ICIs are capable of migrating across the BBB and exerting immune responses in the intraparenchymal tumor microenvironment (TME) of gliomas (37–39). Although a series of phase III trials have failed to show optimal results so far (NCT02017717, NCT02617589 and NCT02667587) (19,40,41), ICIs still hold promise for treatment of gliomas, such as in combination with other immune and non-immune treatments as well as use after optimization of patient selection or neoadjuvant administration as described in this section (42–45). In regard to optimal patient selection, ICI treatment for temozolomide (TMZ)-induced hypermutated GBM has been the subject of debate for years (24,46). Frequent use of TMZ, an alkylating agent used in standard-of-care, often leads to a significant accumulation of single-nucleotide variant (missense) mutations in recurrent tumor compared to non-hypermutated counterparts (median mutation burden: 50.8 vs. 2.6 mutation per Mb) (47). The incidence of hypermutation is estimated to be 10–20% of post-TMZ recurrent tumors (47,48). The strong correlation between efficacy and the tumor mutational burden observed in other cancers (49) as well as several case reports on inherent mismatch repair-deficient patients with hypermutated GBM, who exhibited objective responses to ICI treatment (50,51), have culminated into the above-mentioned hypothesis. However, recent studies have provided opposing data regarding the efficacy of ICI on TMZ-induced hypermutated GBM (47,52). The isocitrate dehydrogenase (IDH) mutation-induced immunosuppressive TME, as well as the sparsity of insertion/deletion/frameshift-type mutations, may preclude ICI efficacy in these tumors (53–55). Currently, in two separate clinical trials, pembrolizumab (anti-PD-1 mAb) and avelumab (anti-PD-L1 mAb) are being prospectively investigated for patients with recurrent hypermutated gliomas/GBMs (NCT02658279, NCT02968940) (56). The studies are expected to bring more robust insight on ICI efficacy in hypermutated GBM. Another interesting strategy involves neoadjuvant (presurgical) administration of ICIs (57). The rationale is to proactively enhance systemic immunity against tumor antigens, eliminating micrometastatic/disseminated tumor cells that would otherwise be the source of future relapse. Another possible advantage includes preventing early exhaustion of tumor-infiltrating leukocytes (TILs) interacting with higher levels of endogenous tumor antigen prior to resection, and thereby enhancing T-cell priming. Cloughesy et al. (43) recently reported the results of a randomized, open-label pilot study of neoadjuvant versus adjuvant pembrolizumab treatment in patients with recurrent GBM. Although the sample size was limited (16 patients each), the study showed a significant improvement in overall and progression-free survival (OS and PFS) in the neoadjuvant group. Of note, the resected tumor specimens in the neoadjuvant group were characterized by enhanced interferon gamma (IFNγ)-related gene signatures and PD-L1 expression. In addition, T-cell receptor (TCR) repertoire sequencing highlighted the gradual overlapping expansion of the T-cell clones between tumor and blood, indicating a coordinated local and systemic T-cell response elicited by neoadjuvant ICI. In the other paper published back-to-back with the above-mentioned literature, Schalper et al. (44) reported a phase-II single-arm trial in which patients with newly diagnosed and recurrent, resectable GBMs were treated with neoadjuvant plus adjuvant nivolumab. Neoadjuvant therapy resulted in (i) enhanced expression of chemokines, (ii) enhanced immune cell infiltration and (iii) augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, indicating a local immunomodulatory effect of treatment. Intriguingly, a variable degree of PD-1 occupancy was observed in the infiltrating T-cells within the resected specimens, providing evidence of their interaction with nivolumab. However, care should be taken in the interpretation of this data. First, both of the above-mentioned studies are early phase exploratory studies with limited cohort size and breadth of patient subtype. Second, while multiple early phase studies on ICI monotherapy had suggested the efficacy in glioma in the past, none of them finally succeeded. Further validation is needed through carefully designed prospective, controlled clinical trials (58). Vaccines for gliomas Unlike those for infectious diseases, tumor vaccines are expected to induce a therapeutic adaptive immune response against a specific antigen rather than a prophylactic response. Among the various forms of tumor vaccines investigated (59) (Table 1 and 2), we specifically focus on peptide vaccines in this review. They can be further classified based on their target antigen type, such as (i) single peptide vaccines targeting shared neoantigens, (ii) multipeptide vaccines employing non-mutant shared antigens and (iii) multipeptide vaccines incorporating private neoantigens. Table 1 Recently completed clinical trials of vaccine for glioma Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Main findings . Phase III NCT01480479 (ACT-IV) (20) EGFRvIII vaccine (Rindopepimut) GM-CSF Multi-center, randomized, double-blind Newly diagnosed EGFRvIII+ GBM 745 OS Median-OS: 20.1 vs 20.0 m (HR 1.01, 95% CI 0.79–1.30; P = 0.93) Phase II NCT01498328 (ReACT) (61) EGFRvIII vaccine (Rindopepimut) + bevacizumab GM-CSF Multi-center, randomized, double-blind Relapsed EGFRvIII+ GBM 73 6 m-PFS 6 m-PFS: 28% for rindopepimut vs 16% for control (P = 0.12, one-sided) NCT01280552 (167) DCs pulsed with 6 synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A1 or A2+ newly diagnosed GBM 124 OS Median-OS: 17.0 vs 15.0 m (HR 0.87, P = 0.58) HLA-A2+ patients showed higher cellular immune response Phase I NCT02454634 (NOA-16) (67) IDH1-R132H peptide vaccine Montanide + imiquimod Single-arm, open-label Grade III-IV glioma with IDH1 R132H mutation 39 Safety Neither RLT nor severe AE were observed. Mutation- specific T-cell or humoral immune response was induced in 80% and 87%, respectively NCT02960230 (PNOC-007) (70,71) H3.3-K27M peptide vaccine Montanide + TT + poly-ICLC 2-arm, open-label H3.3K27M+ pediatric DMG/DIPG 49 Safety, 12 m-OS Seven Grade 3 and zero Grade 4 treatment related AE. 12 m-OS: 40% for DIPG and 39% for other DMG. CyTOF analyses of PBMCs revealed the expansion of mutation-specific CD8+ T-cells NCT01250470 (168) Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF single-arm, open-label Survivin+ relapsed malignant glioma 9 Safety No grade 3–4 vaccine-related AE. Both cellular and humoral immune responses were induced in 75% (6 of 8) NCT01920191 (74) Multi-GAA peptide vaccine (IMA950) Poly-ICLC Single-arm, open-label HLA-A2+ newly diagnosed GBM 19 Safety Four patients developed cerebral edema with rapid recovery. CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8%, respectively. Protocol modification significantly improved vaccine efficacy NCT02149225 (GAPVAC-101) (77) Personalized multi-GAA and neoantigen vaccine (APVAC1/2) Poly-ICLC + GM-CSF Multi-center, open-label HLA-A*02:01+ or 24:02+ newly diagnosed GBM 16 Safety, cellular immune responses Favorable safety and robust immunogenicity were confirmed. APVAC1 and 2 antigens preferrentially induced sustained CD8+ Tcm and CD4+ Th1, respectively Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Main findings . Phase III NCT01480479 (ACT-IV) (20) EGFRvIII vaccine (Rindopepimut) GM-CSF Multi-center, randomized, double-blind Newly diagnosed EGFRvIII+ GBM 745 OS Median-OS: 20.1 vs 20.0 m (HR 1.01, 95% CI 0.79–1.30; P = 0.93) Phase II NCT01498328 (ReACT) (61) EGFRvIII vaccine (Rindopepimut) + bevacizumab GM-CSF Multi-center, randomized, double-blind Relapsed EGFRvIII+ GBM 73 6 m-PFS 6 m-PFS: 28% for rindopepimut vs 16% for control (P = 0.12, one-sided) NCT01280552 (167) DCs pulsed with 6 synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A1 or A2+ newly diagnosed GBM 124 OS Median-OS: 17.0 vs 15.0 m (HR 0.87, P = 0.58) HLA-A2+ patients showed higher cellular immune response Phase I NCT02454634 (NOA-16) (67) IDH1-R132H peptide vaccine Montanide + imiquimod Single-arm, open-label Grade III-IV glioma with IDH1 R132H mutation 39 Safety Neither RLT nor severe AE were observed. Mutation- specific T-cell or humoral immune response was induced in 80% and 87%, respectively NCT02960230 (PNOC-007) (70,71) H3.3-K27M peptide vaccine Montanide + TT + poly-ICLC 2-arm, open-label H3.3K27M+ pediatric DMG/DIPG 49 Safety, 12 m-OS Seven Grade 3 and zero Grade 4 treatment related AE. 12 m-OS: 40% for DIPG and 39% for other DMG. CyTOF analyses of PBMCs revealed the expansion of mutation-specific CD8+ T-cells NCT01250470 (168) Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF single-arm, open-label Survivin+ relapsed malignant glioma 9 Safety No grade 3–4 vaccine-related AE. Both cellular and humoral immune responses were induced in 75% (6 of 8) NCT01920191 (74) Multi-GAA peptide vaccine (IMA950) Poly-ICLC Single-arm, open-label HLA-A2+ newly diagnosed GBM 19 Safety Four patients developed cerebral edema with rapid recovery. CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8%, respectively. Protocol modification significantly improved vaccine efficacy NCT02149225 (GAPVAC-101) (77) Personalized multi-GAA and neoantigen vaccine (APVAC1/2) Poly-ICLC + GM-CSF Multi-center, open-label HLA-A*02:01+ or 24:02+ newly diagnosed GBM 16 Safety, cellular immune responses Favorable safety and robust immunogenicity were confirmed. APVAC1 and 2 antigens preferrentially induced sustained CD8+ Tcm and CD4+ Th1, respectively GM-CSF, granulocyte macrophage colony-stimulating factor; GBM, glioblastoma; OS, overall survival; PFS, progression-free survival; DC, dendritic cell; GAA, glioma-associated antigen; RLT, regime-limiting toxicity; TT, tetanus toxoid peptide; Tcm, central memory T; Th1, helper 1 type T. Open in new tab Table 1 Recently completed clinical trials of vaccine for glioma Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Main findings . Phase III NCT01480479 (ACT-IV) (20) EGFRvIII vaccine (Rindopepimut) GM-CSF Multi-center, randomized, double-blind Newly diagnosed EGFRvIII+ GBM 745 OS Median-OS: 20.1 vs 20.0 m (HR 1.01, 95% CI 0.79–1.30; P = 0.93) Phase II NCT01498328 (ReACT) (61) EGFRvIII vaccine (Rindopepimut) + bevacizumab GM-CSF Multi-center, randomized, double-blind Relapsed EGFRvIII+ GBM 73 6 m-PFS 6 m-PFS: 28% for rindopepimut vs 16% for control (P = 0.12, one-sided) NCT01280552 (167) DCs pulsed with 6 synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A1 or A2+ newly diagnosed GBM 124 OS Median-OS: 17.0 vs 15.0 m (HR 0.87, P = 0.58) HLA-A2+ patients showed higher cellular immune response Phase I NCT02454634 (NOA-16) (67) IDH1-R132H peptide vaccine Montanide + imiquimod Single-arm, open-label Grade III-IV glioma with IDH1 R132H mutation 39 Safety Neither RLT nor severe AE were observed. Mutation- specific T-cell or humoral immune response was induced in 80% and 87%, respectively NCT02960230 (PNOC-007) (70,71) H3.3-K27M peptide vaccine Montanide + TT + poly-ICLC 2-arm, open-label H3.3K27M+ pediatric DMG/DIPG 49 Safety, 12 m-OS Seven Grade 3 and zero Grade 4 treatment related AE. 12 m-OS: 40% for DIPG and 39% for other DMG. CyTOF analyses of PBMCs revealed the expansion of mutation-specific CD8+ T-cells NCT01250470 (168) Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF single-arm, open-label Survivin+ relapsed malignant glioma 9 Safety No grade 3–4 vaccine-related AE. Both cellular and humoral immune responses were induced in 75% (6 of 8) NCT01920191 (74) Multi-GAA peptide vaccine (IMA950) Poly-ICLC Single-arm, open-label HLA-A2+ newly diagnosed GBM 19 Safety Four patients developed cerebral edema with rapid recovery. CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8%, respectively. Protocol modification significantly improved vaccine efficacy NCT02149225 (GAPVAC-101) (77) Personalized multi-GAA and neoantigen vaccine (APVAC1/2) Poly-ICLC + GM-CSF Multi-center, open-label HLA-A*02:01+ or 24:02+ newly diagnosed GBM 16 Safety, cellular immune responses Favorable safety and robust immunogenicity were confirmed. APVAC1 and 2 antigens preferrentially induced sustained CD8+ Tcm and CD4+ Th1, respectively Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Main findings . Phase III NCT01480479 (ACT-IV) (20) EGFRvIII vaccine (Rindopepimut) GM-CSF Multi-center, randomized, double-blind Newly diagnosed EGFRvIII+ GBM 745 OS Median-OS: 20.1 vs 20.0 m (HR 1.01, 95% CI 0.79–1.30; P = 0.93) Phase II NCT01498328 (ReACT) (61) EGFRvIII vaccine (Rindopepimut) + bevacizumab GM-CSF Multi-center, randomized, double-blind Relapsed EGFRvIII+ GBM 73 6 m-PFS 6 m-PFS: 28% for rindopepimut vs 16% for control (P = 0.12, one-sided) NCT01280552 (167) DCs pulsed with 6 synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A1 or A2+ newly diagnosed GBM 124 OS Median-OS: 17.0 vs 15.0 m (HR 0.87, P = 0.58) HLA-A2+ patients showed higher cellular immune response Phase I NCT02454634 (NOA-16) (67) IDH1-R132H peptide vaccine Montanide + imiquimod Single-arm, open-label Grade III-IV glioma with IDH1 R132H mutation 39 Safety Neither RLT nor severe AE were observed. Mutation- specific T-cell or humoral immune response was induced in 80% and 87%, respectively NCT02960230 (PNOC-007) (70,71) H3.3-K27M peptide vaccine Montanide + TT + poly-ICLC 2-arm, open-label H3.3K27M+ pediatric DMG/DIPG 49 Safety, 12 m-OS Seven Grade 3 and zero Grade 4 treatment related AE. 12 m-OS: 40% for DIPG and 39% for other DMG. CyTOF analyses of PBMCs revealed the expansion of mutation-specific CD8+ T-cells NCT01250470 (168) Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF single-arm, open-label Survivin+ relapsed malignant glioma 9 Safety No grade 3–4 vaccine-related AE. Both cellular and humoral immune responses were induced in 75% (6 of 8) NCT01920191 (74) Multi-GAA peptide vaccine (IMA950) Poly-ICLC Single-arm, open-label HLA-A2+ newly diagnosed GBM 19 Safety Four patients developed cerebral edema with rapid recovery. CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8%, respectively. Protocol modification significantly improved vaccine efficacy NCT02149225 (GAPVAC-101) (77) Personalized multi-GAA and neoantigen vaccine (APVAC1/2) Poly-ICLC + GM-CSF Multi-center, open-label HLA-A*02:01+ or 24:02+ newly diagnosed GBM 16 Safety, cellular immune responses Favorable safety and robust immunogenicity were confirmed. APVAC1 and 2 antigens preferrentially induced sustained CD8+ Tcm and CD4+ Th1, respectively GM-CSF, granulocyte macrophage colony-stimulating factor; GBM, glioblastoma; OS, overall survival; PFS, progression-free survival; DC, dendritic cell; GAA, glioma-associated antigen; RLT, regime-limiting toxicity; TT, tetanus toxoid peptide; Tcm, central memory T; Th1, helper 1 type T. Open in new tab Vaccines targeting shared neoantigens originating from common mutations in gliomas, such as IDH1-R132H, H3.3-K27M and EGFRvIII, have been widely studied (24). One notable example, EGFRvIII, showed promise in preclinical and early phase trials (60); however, advanced phase (II/III) studies with the EGFRvIII vaccine, rindopepimut (CDX-110), have failed to show survival benefit for patients with newly diagnosed (ACT IV, NCT01480479) (20) and relapsed GBM (ReACT, NCT01498328) (61). Antigen loss was indeed observed in post-treatment specimens in the study, indicating cancer immunoediting as a result of effective treatment (62,63). On the other hand, IDH1-R132 and H3.3-K27M are truncal mutations, thus all tumor cells typically retain the mutant peptides (64), which is ideal in terms of immunotherapy, with rare exceptions of transient loss of IDH-mutations (65). Schumacher et al. (66) developed a peptide vaccine encompassing the IDH1-R132H mutation capable of inducing both epitope-specific CD4+ T-helper-cell responses (TH1) as well as humoral responses. Two separate first-in-human phase I trials with IDH1-R132H vaccines, NOA-16 (NCT02454634) and RESIST (NCT02193347), are currently ongoing (67). NOA-16 has so far shown optimal results in terms of safety as well as induction of cellular and humoral immunity (67). In pediatric DMGs/DIPGs, the H3.3-K27M mutation-derived epitope bound to HLA-A*02:01 was concurrently identified by two research groups (68,69). A first-in-human pilot clinical trial of H3.3-K27M peptide vaccine in patients with newly diagnosed DMGs (PNOC-007 trial, NCT02960230) was recently completed. Preliminary results showed the safety, the successful induction of antigen-specific T-cells in peripheral blood mononuclear cells (PBMCs), and a correlation between elicited adaptive immune response and survival benefit (70,71). Multipeptide vaccines targeting non-mutant antigens is another strategy that holds several advantages over single antigen and neoantigen vaccines, including preconfirmed immunogenicity and the clinical feasibility of the off-the-shelf approach. One recent example is IMA950, composed of 11 tumor-associated antigens, of which robust immunogenicity had been previously demonstrated in the context of HLA-A2 (72). A single-arm, phase I/II study, demonstrated not only feasible tolerability, but also an improved survival benefit in the IMA950/poly-ICLC protocol compared with IMA950/granulocyte macrophage colony-stimulating factor (GM-CSF) used in the previous study (NCT01920191) (73,74). Interestingly, the researchers amended the vaccine administration route from intradermal (i.d.) to intramuscular (i.m.) or subcutaneous (s.c.) injections in the middle of the study, significantly improving the induction of CD8+ and CD4+ T-cell responses. The vaccine is currently being investigated in combination with varlilumab (anti-CD27-mAb) (NCT02924038) and with pembrolizumab (NCT03665545). Narita et al. (75) recently reported another study of multiple peptide vaccines conducted in Japan. In this randomized, double-blinded, phase-III trial, 58 HLA-A24+ patients were administered 4 out of 12 warehouse peptides (ITK-1) carefully chosen based on their baseline peptide-specific IgG responses (76). Although the study failed to show survival benefits, interestingly, the selection of one warehouse peptide (SART2–93) significantly correlated with shorter survival and poorer cellular immunity compared with the others. Another recent advancement involves a more personalized approach, through the targeting of private neoantigens—tumor-specific protein-coding mutations—on an individual basis. In 2019, Hilf et al. (77) reported the results of a phase I GAPVAC-101 trial (NCT02149225), in which 15 HLA-A*02:01 or 24:02 patients with newly diagnosed GBM were treated with the ‘personalized’ vaccine cocktails. This study employed two separate steps of antigen selection for the actively personalized vaccine 1 (APVAC1) and APVAC2. For APVAC1, 6–7 antigens were carefully selected from a warehouse of pre-manufactured, non-mutant HLA class-I peptides and administered together with GM-CSF and poly-ICLC (78). For APVAC2, the neoantigens were preferentially selected based on transcriptome, HLA class I peptidome and pre-vaccine T-cell reactivity tests on an individual basis while the ligandome-based approach failed in neoantigen detection in this study cohort (79). The overall results from the GAPVAC-101 trial were encouraging in terms of safety as well as inducement of robust immunogenicity. In particular, an induction of APVAC1-antigen-reactive CD8+ T-cells was observed in PBMCs from most patients, accompanied by a shift to a memory phenotype. On the other hand, neoantigen vaccines in APVAC2 preferentially induced a CD4+ T-cell response. In another paper published back-to-back with the above-mentioned literature, Keskin et al. (80) also reported encouraging results from their phase I/Ib study of a personalized neoantigen vaccine (NeoVax study, NCT02287428). Using entirely in silico neoantigen prediction, 8 patients with newly diagnosed GBM were treated with a median of 12 synthetic peptides. Of note, two patients, not requiring dexamethasone during the vaccine-priming period, exhibited robust de novo T-cell responses against multiple neoantigens. CD8+ and CD4+ T-cells were both induced and enriched in an antigen-experienced memory phenotype with poly-functionality. In addition, post-vaccine tumor specimens from these two patients showed significant increases in tumor-infiltrating T-cells. TCR repertoire analyses revealed that a fraction of neoantigen-reactive T-cell clonotypes was shared between the post-vaccine tumor and blood samples, with increased frequency in the tumor, indicating the successful trafficking of vaccine-induced neoantigen-reactive T-cells to the tumor site. Table 2 Ongoing clinical trials of vaccines for glioma Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Status . Phase III NCT02546102 (STING) DCs pulsed with six synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A2+ newly diagnosed GBM 414 OS Suspended NCT00045968 (DCVax-L) (169) DCs pulsed with autologous tumor lysate - Multi-center, randomized, double-blind, placebo-controlled Newly diagnosed GBM 348 PFS Unknown Phase II NCT02455557 Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF Multi-center, open-label Survivin+ newly diagnosed GBM 64 6 m-PFS Active NCT04013672 Survivin peptide vaccine (SurVaxM) + pembrolizumab Montanide + GM-CSF Single-arm, open-label Relapsed GBM 51 6 m-PFS Recruiting NCT01204684 DCs pulsed with autologous tumor lysate Resiquimod or poly-ICLC Randomized, open-label Newly diagnosed grade III-IV glioma 60 Most effective combination Active Phase I NCT02193347 (RESIST) IDH1 R132H peptide vaccine (PEPIDH1M) Td Single-arm, open-label Grade II, relapsed glioma with IDH1 R132H mutation 24 Safety Active NCT02924038 Multi-GAA peptide vaccine (IMA950) + neoadjuvant varlilumab Poly-ICLC Randomized, open-label HLA-A2+ grade II glioma 30 Safety, cellular immune responce Recruiting NCT03665545 (IMA950–106) Multi-GAA peptide vaccine (IMA950) + pembrolizumab Poly-ICLC Randomized, open-label HLA-A*02:01+ relapsed GBM 24 Safety Recruiting NCT02287428 (NeoVax) (80) Personalized neoantigen vaccine + pembrolizumab (later added) - 4-Arm, randomized, open-label Newly diagnosed GBM 56 Safety Active Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Status . Phase III NCT02546102 (STING) DCs pulsed with six synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A2+ newly diagnosed GBM 414 OS Suspended NCT00045968 (DCVax-L) (169) DCs pulsed with autologous tumor lysate - Multi-center, randomized, double-blind, placebo-controlled Newly diagnosed GBM 348 PFS Unknown Phase II NCT02455557 Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF Multi-center, open-label Survivin+ newly diagnosed GBM 64 6 m-PFS Active NCT04013672 Survivin peptide vaccine (SurVaxM) + pembrolizumab Montanide + GM-CSF Single-arm, open-label Relapsed GBM 51 6 m-PFS Recruiting NCT01204684 DCs pulsed with autologous tumor lysate Resiquimod or poly-ICLC Randomized, open-label Newly diagnosed grade III-IV glioma 60 Most effective combination Active Phase I NCT02193347 (RESIST) IDH1 R132H peptide vaccine (PEPIDH1M) Td Single-arm, open-label Grade II, relapsed glioma with IDH1 R132H mutation 24 Safety Active NCT02924038 Multi-GAA peptide vaccine (IMA950) + neoadjuvant varlilumab Poly-ICLC Randomized, open-label HLA-A2+ grade II glioma 30 Safety, cellular immune responce Recruiting NCT03665545 (IMA950–106) Multi-GAA peptide vaccine (IMA950) + pembrolizumab Poly-ICLC Randomized, open-label HLA-A*02:01+ relapsed GBM 24 Safety Recruiting NCT02287428 (NeoVax) (80) Personalized neoantigen vaccine + pembrolizumab (later added) - 4-Arm, randomized, open-label Newly diagnosed GBM 56 Safety Active Td, tetanus-diphtheria toxoid. Open in new tab Table 2 Ongoing clinical trials of vaccines for glioma Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Status . Phase III NCT02546102 (STING) DCs pulsed with six synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A2+ newly diagnosed GBM 414 OS Suspended NCT00045968 (DCVax-L) (169) DCs pulsed with autologous tumor lysate - Multi-center, randomized, double-blind, placebo-controlled Newly diagnosed GBM 348 PFS Unknown Phase II NCT02455557 Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF Multi-center, open-label Survivin+ newly diagnosed GBM 64 6 m-PFS Active NCT04013672 Survivin peptide vaccine (SurVaxM) + pembrolizumab Montanide + GM-CSF Single-arm, open-label Relapsed GBM 51 6 m-PFS Recruiting NCT01204684 DCs pulsed with autologous tumor lysate Resiquimod or poly-ICLC Randomized, open-label Newly diagnosed grade III-IV glioma 60 Most effective combination Active Phase I NCT02193347 (RESIST) IDH1 R132H peptide vaccine (PEPIDH1M) Td Single-arm, open-label Grade II, relapsed glioma with IDH1 R132H mutation 24 Safety Active NCT02924038 Multi-GAA peptide vaccine (IMA950) + neoadjuvant varlilumab Poly-ICLC Randomized, open-label HLA-A2+ grade II glioma 30 Safety, cellular immune responce Recruiting NCT03665545 (IMA950–106) Multi-GAA peptide vaccine (IMA950) + pembrolizumab Poly-ICLC Randomized, open-label HLA-A*02:01+ relapsed GBM 24 Safety Recruiting NCT02287428 (NeoVax) (80) Personalized neoantigen vaccine + pembrolizumab (later added) - 4-Arm, randomized, open-label Newly diagnosed GBM 56 Safety Active Clinical trial ID . Active treatment . Adjuvant . Study design . Study subject . N . Primary endpoint . Status . Phase III NCT02546102 (STING) DCs pulsed with six synthetic GAA peptides (ICT-107) - Multi-center, randomized, double-blind, placebo-controlled HLA-A2+ newly diagnosed GBM 414 OS Suspended NCT00045968 (DCVax-L) (169) DCs pulsed with autologous tumor lysate - Multi-center, randomized, double-blind, placebo-controlled Newly diagnosed GBM 348 PFS Unknown Phase II NCT02455557 Survivin peptide vaccine (SurVaxM) Montanide + GM-CSF Multi-center, open-label Survivin+ newly diagnosed GBM 64 6 m-PFS Active NCT04013672 Survivin peptide vaccine (SurVaxM) + pembrolizumab Montanide + GM-CSF Single-arm, open-label Relapsed GBM 51 6 m-PFS Recruiting NCT01204684 DCs pulsed with autologous tumor lysate Resiquimod or poly-ICLC Randomized, open-label Newly diagnosed grade III-IV glioma 60 Most effective combination Active Phase I NCT02193347 (RESIST) IDH1 R132H peptide vaccine (PEPIDH1M) Td Single-arm, open-label Grade II, relapsed glioma with IDH1 R132H mutation 24 Safety Active NCT02924038 Multi-GAA peptide vaccine (IMA950) + neoadjuvant varlilumab Poly-ICLC Randomized, open-label HLA-A2+ grade II glioma 30 Safety, cellular immune responce Recruiting NCT03665545 (IMA950–106) Multi-GAA peptide vaccine (IMA950) + pembrolizumab Poly-ICLC Randomized, open-label HLA-A*02:01+ relapsed GBM 24 Safety Recruiting NCT02287428 (NeoVax) (80) Personalized neoantigen vaccine + pembrolizumab (later added) - 4-Arm, randomized, open-label Newly diagnosed GBM 56 Safety Active Td, tetanus-diphtheria toxoid. Open in new tab Cellular immunotherapy for gliomas Compared to ICIs and vaccines, cellular immunotherapy is a more straightforward approach, as preactivated T-cells will be directed to the tumor bed after infusion. Although TIL therapy has shown high-objective response rates in metastatic melanoma (81), its applications in primary brain tumors are limited (82,83), possibly owing to the sparsity of TILs and tumor-specific antigens. Instead, several modes of genetically engineered cellular immunotherapies have been actively investigated in gliomas, including CAR-T targeting cell-surface antigens, such as IL13Rα2 (84), HER2 (85), EphA2 (86) and EGFRvIII (87) as well as TCR-T-cell therapy targeting intracellular antigens like H3.3-K27M (69). Brown et al. (88) conducted a phase I trial of IL13Rα2-directed CAR-T with various administration routes for patients with recurrent malignant gliomas, in which a representative case exhibited a dramatic and sustained clinical response after intraventricular infusion (NCT02208362). Recently, the researchers initiated another phase I trial to test the therapy in combination with ICIs (NCT04003649). An emerging cell-surface target for CAR-T is disialoganglioside (GD2) (89). Its expression is primarily restricted to the CNS after birth whereas its aberrant expression is observed in some neuroectodermal-origin tumors, such as melanoma (90) and neuroblastoma (91). Owing to its high tumor specificity, immunotherapy targeting GD2 has been investigated since the 1980s mainly for neuroblastoma (92). Rossig et al. (93) first described a GD2-targeting CAR-T. Although GD2 is expressed on neurons at low levels, neurotoxicity has not been observed clinically (94–96). Encouraged by these studies, Mount et al. (97) found uniformly high expression of GD2 in patient-derived H3-K27M-mutant DIPG cultures, which was even higher than neuroblastoma and sarcoma cell lines. By contrast, the expression was far lower in H3 wild-type DIPG cultures. The researchers also developed a GD2-CAR-T for DIPG and tested its cytotoxicity in xenograft preclinical models. The CAR-T eradicated H3 K27M-mutant tumors in a GD2-dependent manner both in vitro and in vivo. In May 2020, a phase I clinical trial started enrolling patients for the treatment of DIPGs and spinal DMGs with the GD2-CAR-T (NCT04196413). Other such representative, ongoing clinical trials are summarized in Table 3. Table 3 Ongoing clinical trials of genetically-engineered cellular immunotherapy for glioma Clinical trial ID . Active treatment . Administration route . Study subject . N . Primary endpoint . Status . Phase I NCT04196413 (97) GD2 CAR N/A H3K27M-DMG/DIPG 54 Feasibility, MTD, safety Recruiting NCT02208362 (88) IL13Rα2 CAR Intratumoral or intracavitary or intraventricular Recurrent grade III-IV glioma 92 Safety Recruiting NCT04185038 B7H3 CAR Intracavitary or intraventricular Recurrent CNS tumor or DMG/DIPG 70 Safety and feasibility Recruiting NCT03500991 HER2 CAR Intracavitary (arm A) or intraventricular (arm B) HER2+ recurrent pediatric CNS tumor 48 Safety and feasibility Recruiting NCT03638167 EGFR806-specific CAR Intracavitary (arm A) or intraventricular (arm B) Recurrent EGFR+ CNS tumors 36 Safety and feasibility Recruiting NCT04077866 B7H3 CAR Intratumoral or intraventricular Recurrent GBM 40 OS Recruiting NCT04003649 IL13Rα2 CAR + nivolumab +/− ipilimumab Intracavitary or intraventricular Recurrent GBM 60 Safety, feasibility, and 9 m-survival Recruiting NCT04045847 CD147 CAR Intracavitary Recurrent GBM 31 Safety Recruiting NCT04214392 (170) Chrolotoxin (CLTX) CAR Intracranial (dual delivery) MMP2+ recurrent GBM 36 Safety Recruiting NCT03726515 EGFRvIII CAR + pembrolizumab Intravenous Newly diagnosed, EGFRvIII+, MGMT-unmethylated GBM 7 Safety Recruiting NCT02442297 HER2 CAR Intracranial HER2+ recurrent CNS tumors, pediatric and adult 28 Safety Recruiting NCT03412877 Mutated neoantigen TCR (virally engineered) +/− pembrolizumab intravenous GBM and other types of cancer 270 Response rate Recruiting NCT04102436 Mutated neoantigen TCR (non-virally engineered) intravenous GBM and other types of cancer 210 Response rate Recruiting Clinical trial ID . Active treatment . Administration route . Study subject . N . Primary endpoint . Status . Phase I NCT04196413 (97) GD2 CAR N/A H3K27M-DMG/DIPG 54 Feasibility, MTD, safety Recruiting NCT02208362 (88) IL13Rα2 CAR Intratumoral or intracavitary or intraventricular Recurrent grade III-IV glioma 92 Safety Recruiting NCT04185038 B7H3 CAR Intracavitary or intraventricular Recurrent CNS tumor or DMG/DIPG 70 Safety and feasibility Recruiting NCT03500991 HER2 CAR Intracavitary (arm A) or intraventricular (arm B) HER2+ recurrent pediatric CNS tumor 48 Safety and feasibility Recruiting NCT03638167 EGFR806-specific CAR Intracavitary (arm A) or intraventricular (arm B) Recurrent EGFR+ CNS tumors 36 Safety and feasibility Recruiting NCT04077866 B7H3 CAR Intratumoral or intraventricular Recurrent GBM 40 OS Recruiting NCT04003649 IL13Rα2 CAR + nivolumab +/− ipilimumab Intracavitary or intraventricular Recurrent GBM 60 Safety, feasibility, and 9 m-survival Recruiting NCT04045847 CD147 CAR Intracavitary Recurrent GBM 31 Safety Recruiting NCT04214392 (170) Chrolotoxin (CLTX) CAR Intracranial (dual delivery) MMP2+ recurrent GBM 36 Safety Recruiting NCT03726515 EGFRvIII CAR + pembrolizumab Intravenous Newly diagnosed, EGFRvIII+, MGMT-unmethylated GBM 7 Safety Recruiting NCT02442297 HER2 CAR Intracranial HER2+ recurrent CNS tumors, pediatric and adult 28 Safety Recruiting NCT03412877 Mutated neoantigen TCR (virally engineered) +/− pembrolizumab intravenous GBM and other types of cancer 270 Response rate Recruiting NCT04102436 Mutated neoantigen TCR (non-virally engineered) intravenous GBM and other types of cancer 210 Response rate Recruiting CAR, chimeric antigen receptor; DMG, diffuse midline glioma; DIPG, diffuse intrinsic pontine glioma; MTD, maximum tolerated dose; CNS, central nervous system; MMP2, metalloproteinase; MGMT, O-6-methylguanine-DNA methyltransferase; TCR, T-cell receptor. Open in new tab Table 3 Ongoing clinical trials of genetically-engineered cellular immunotherapy for glioma Clinical trial ID . Active treatment . Administration route . Study subject . N . Primary endpoint . Status . Phase I NCT04196413 (97) GD2 CAR N/A H3K27M-DMG/DIPG 54 Feasibility, MTD, safety Recruiting NCT02208362 (88) IL13Rα2 CAR Intratumoral or intracavitary or intraventricular Recurrent grade III-IV glioma 92 Safety Recruiting NCT04185038 B7H3 CAR Intracavitary or intraventricular Recurrent CNS tumor or DMG/DIPG 70 Safety and feasibility Recruiting NCT03500991 HER2 CAR Intracavitary (arm A) or intraventricular (arm B) HER2+ recurrent pediatric CNS tumor 48 Safety and feasibility Recruiting NCT03638167 EGFR806-specific CAR Intracavitary (arm A) or intraventricular (arm B) Recurrent EGFR+ CNS tumors 36 Safety and feasibility Recruiting NCT04077866 B7H3 CAR Intratumoral or intraventricular Recurrent GBM 40 OS Recruiting NCT04003649 IL13Rα2 CAR + nivolumab +/− ipilimumab Intracavitary or intraventricular Recurrent GBM 60 Safety, feasibility, and 9 m-survival Recruiting NCT04045847 CD147 CAR Intracavitary Recurrent GBM 31 Safety Recruiting NCT04214392 (170) Chrolotoxin (CLTX) CAR Intracranial (dual delivery) MMP2+ recurrent GBM 36 Safety Recruiting NCT03726515 EGFRvIII CAR + pembrolizumab Intravenous Newly diagnosed, EGFRvIII+, MGMT-unmethylated GBM 7 Safety Recruiting NCT02442297 HER2 CAR Intracranial HER2+ recurrent CNS tumors, pediatric and adult 28 Safety Recruiting NCT03412877 Mutated neoantigen TCR (virally engineered) +/− pembrolizumab intravenous GBM and other types of cancer 270 Response rate Recruiting NCT04102436 Mutated neoantigen TCR (non-virally engineered) intravenous GBM and other types of cancer 210 Response rate Recruiting Clinical trial ID . Active treatment . Administration route . Study subject . N . Primary endpoint . Status . Phase I NCT04196413 (97) GD2 CAR N/A H3K27M-DMG/DIPG 54 Feasibility, MTD, safety Recruiting NCT02208362 (88) IL13Rα2 CAR Intratumoral or intracavitary or intraventricular Recurrent grade III-IV glioma 92 Safety Recruiting NCT04185038 B7H3 CAR Intracavitary or intraventricular Recurrent CNS tumor or DMG/DIPG 70 Safety and feasibility Recruiting NCT03500991 HER2 CAR Intracavitary (arm A) or intraventricular (arm B) HER2+ recurrent pediatric CNS tumor 48 Safety and feasibility Recruiting NCT03638167 EGFR806-specific CAR Intracavitary (arm A) or intraventricular (arm B) Recurrent EGFR+ CNS tumors 36 Safety and feasibility Recruiting NCT04077866 B7H3 CAR Intratumoral or intraventricular Recurrent GBM 40 OS Recruiting NCT04003649 IL13Rα2 CAR + nivolumab +/− ipilimumab Intracavitary or intraventricular Recurrent GBM 60 Safety, feasibility, and 9 m-survival Recruiting NCT04045847 CD147 CAR Intracavitary Recurrent GBM 31 Safety Recruiting NCT04214392 (170) Chrolotoxin (CLTX) CAR Intracranial (dual delivery) MMP2+ recurrent GBM 36 Safety Recruiting NCT03726515 EGFRvIII CAR + pembrolizumab Intravenous Newly diagnosed, EGFRvIII+, MGMT-unmethylated GBM 7 Safety Recruiting NCT02442297 HER2 CAR Intracranial HER2+ recurrent CNS tumors, pediatric and adult 28 Safety Recruiting NCT03412877 Mutated neoantigen TCR (virally engineered) +/− pembrolizumab intravenous GBM and other types of cancer 270 Response rate Recruiting NCT04102436 Mutated neoantigen TCR (non-virally engineered) intravenous GBM and other types of cancer 210 Response rate Recruiting CAR, chimeric antigen receptor; DMG, diffuse midline glioma; DIPG, diffuse intrinsic pontine glioma; MTD, maximum tolerated dose; CNS, central nervous system; MMP2, metalloproteinase; MGMT, O-6-methylguanine-DNA methyltransferase; TCR, T-cell receptor. Open in new tab Viral immunotherapy for gliomas Oncolytic viruses (OV) not only have cytolytic effects on cancer cells but also trigger various pro-inflammatory signals, which recruit cytotoxic T-cells to the TME (98). Therefore, OV therapies are designed with the expectation of inciting direct tumor-targeted oncolysis as well as acting as an in situ tumor vaccination. Among a variety of viral immunotherapy currently investigated in gliomas (99,100), we briefly touch on the following: adenovirus (DNX-2401/-2440), herpes simplex virus-1 (HSV-1) (G207 and G47∆), and retroviral replicating vector (RRV) (Toca-511/5-FC), all of which have demonstrated the most remarkable advances in both preclinical and clinical investigation. Adenovirus (DNX-2401) DNX-2401 (originally delta-24-RGD) is a second generation conditionally replicative oncolytic adenovirus (CRAd) designed to selectively replicate in tumor cells with Rb pathway dysregulation (101). In a phase I trial (NCT00805376), DNX-2401 was administered to patients with recurrent, high-grade gliomas via intratumoral injection alone (group A) or followed 2 weeks later by en bloc tumor resection (group B). A sufficient safety profile as well as clinical efficacy with a 3-year survival rate of 20% was demonstrated in group A. In group B, successful spread and replication of the virus and induction of an antitumor immune response were confirmed in 55% of the post-treatment tumor specimens (102). A variety of phase I-II clinical trials have been subsequently conducted, in combination with dose-dense TMZ (NCT01956734), pembrolizumab (NCT02798406) (103), IFNγ (NCT02197169) (102) and mesenchymal or neural stem cell delivery (NCT03896568, NCT03072134) (104,105). In addition, preclinical models of pediatric high-grade glioma or DIPG have shown that DNX-2401 enhanced radio-sensitivity and increased both CD4+ and CD8+ T-cell infiltration, providing a rationale for combination therapy with radiotherapy (RT) (106,107). Based on this evidence, a phase I trial combining these treatments was conducted for a small cohort of pediatric DIPG patients and completed in April 2020 with results yet to be reported (NCT03178032). Moreover, a third generation, DNX-2440 (or Delta-24-RGDOX) was recently developed, and is now being tested in a phase I trial (NCT03714334) (108). HSV-1 (G207 and G47∆) A second-generation HSV-1, G207, in which the viral ribonucleotide reductase (RR) is inactivated so that replication of G207 is limited to dividing cells, has been tested for more than two decades (109). Subsequent to a series of phase I/Ib trials (NCT00028158) (110,111), Ring et al. (112) reported that a variety of aggressive pediatric brain tumor cells were more sensitive to G207 (by 22-fold) than adult GBM due to significantly higher levels of the virus-entry receptor, CD111 (nectin-1). Encouraged by this finding, G207 is currently being tested in two phase I clinical trials with or without RT in pediatric patients with recurrent/progressive malignant brain tumors (NCT02457845 and NCT03911388) (113). A third-generation HSV-1, G47∆, was developed by Todo et al. (114). A modification of G207 through a deletion in the alpha47 gene resulted in enhanced viral replication, immediate oncolytic activity and improved stimulation of TILs. Following a phase I/IIa trial (UMIN000002661) confirming safety, a phase II trial was conducted for patients with residual or recurrent GBM (UMIN000015995), in which G47∆ was stereotactically and repeatedly injected into the tumor ~6 times. A 1-year survival rate of 92.3% was shown in the interim analysis, leading to early termination of the trial as it fulfilled predetermined criteria (115). R‌RV (Toca 511/Toca FC) Toca 511 (vocimagene amiretrorepvec)/Toca FC is the most advanced viral immunotherapy for treatment of glioma in terms of development and clinical trial phase. Toca 511 has an RRV backbone containing a yeast-derived cytosine deaminase (CD) transgene (116). This treatment strategy is described as prodrug-activator gene therapy since the major role of the Toca 511 RRV is to convert the infected cells into stable, vector-producing cells through integration of the CD gene into the tumor cell genome (117). The expressed CD enzyme intracellularly converts the anti-fungal pro-drug, 5-fluorocytosine (5-FC, administered as Toca FC) into the anticancer drug, 5-fluorouracil (5-FU). Preclinical studies provide evidence of a significant improvement of survival as well as favorable changes in antitumor immunity, such as a reduction of immunosuppressive myeloid cells, polarization away from TH2 and TH17 in CD4+ T-cells and an increase of IFNγ-expressing CD8+ T-cells (116,118,119). Three phase I clinical trials showed a tolerable safety profile and improved survival benefit as compared with external controls, while overall viral loads were controlled systematically (NCT01156584, NCT01470794 and NCT01985256) (120–122). Recently, a phase 2/3 trial was conducted, in which Toca 511 was directly injected into the tumor resection cavity and Toca FC was initiated at 6 weeks post-surgery (NCT02414165). This study, however, was terminated in 2019 after failing to meet both primary and secondary endpoints, the improvement of OS and objective responses in the treatment group as compared with the standard-of-care group (median OS: 11.1 vs 12.2 months), while final results are yet to be published as of June 2020 (123). Although another phase II/III clinical trial involving Toca 511 (NRG-BN006) had been prepared for patients with newly diagnosed GBMs, it was later withdrawn, possibly owing to the failure of the aforementioned study. Recent advances for brain metastases In this section, we overview the current status of ICIs and cellular immunotherapies for BMs. In the past, clinical studies with chemotherapeutic agents as well as immunotherapies had generally excluded patients with BMs from participation. However, this notion has been eventually revised as described in following sections. ICIs for brain metastases In contrast to gliomas, the efficacy of ICIs is nowadays well-acknowledged for BMs. A retrospective analysis of a phase III trial of ipilimumab (anti-CTLA-4 mAb) for advanced melanomas, unexpectedly found that the treatment efficacy was comparable between patients with and without BMs (16). This observation was further supported by a series of prospective and retrospective studies (124–127). A subsequent phase II, prospective study with pembrolizumab was conducted for patients with melanoma or non–small-cell lung cancer (NSCLC) BMs, and showed durable objective responses of 22% and 33%, respectively (NCT02085070) (128). Long-term follow-up data for the 34 patients in NSCLC cohort reported a CNS response rate of 29.4% and a 2-year OS rate of 31% (17). CheckMate-204, a phase II study of ipilimumab and nivolumab for patients with BMs of melanoma (NCT02320058), showed an intracranial response rate of 57%, including a complete response rate of 26% (18). Of note, intra- and extra-cranial responses were highly concordant. Similar findings were reported in another phase II study on BMs of melanoma conducted in Australia (ABC trial, NCT02374242) (129). To further validate these findings, a randomized phase III study testing (i) fotemustine (a nitrosourea alkylating agent) alone vs. (ii) fotemustine and ipilimumab or (iii) ipilimumab and nivolumab is currently ongoing for patients with melanoma BMs (NIBIT-M2 trial, NCT02460068). Cellular immunotherapy for brain metastases Progress has also been made using cellular immunotherapies for treatment of BMs. For example, Priceman et al. (130) investigated their HER2-CAR-T for treatment of breast cancer BMs in preclinical models. This treatment strategy is motivated by the observation that BMs occur in ~50% of HER2+ breast cancer patients. It was hypothesized that a cellular immunotherapy approach could cross the BBB, overcoming the challenge observed in HER2-targeted mAbs. As previous clinical studies have demonstrated safety and efficacy of systemic administration of HER2-CAR-T in patients with sarcoma and recurrent GBM (131,132), the authors sought to optimize the administration routes, the CAR constructs, preconditioning and the dose. In their xenograft mice models, trastuzumab-based HER2-BBζ CAR-T successfully eradicated HER2+ breast cancer BMs after local intratumoral or regional intraventricular delivery while systemic administration was significantly less effective. Interestingly, intraventricular delivery showed robust antitumor activity even against multifocal disease and leptomeningeal spread, which is a relatively common issue in metastatic breast cancer. Based on the therapeutic efficacy in this preclinical study, a phase I clinical trial was recently launched in which HER2-positive breast cancer patients with BMs and/or leptomeningeal carcinomatosis are administered local or regional delivery of HER2-CAR-T (NCT03696030). Immunotherapy for primary and secondary brain tumors: the contrariety in efficacy As described in previous section, the development of successful immunotherapies for glioma is far behind many other types of tumors. On the other hand, the efficacy of ICIs and cellular therapies has been recognized to be comparable between intra- and extra-cranial lesions for the treatment of melanoma or lung cancer BMs. Why is there such a disparity in efficacy with similar therapeutics in tumors that both occur in the CNS? An explanation could be contrived from commonly acknowledged major obstacles to therapy for gliomas including (i) the paucity of and spatial, temporal and intertumoral heterogeneity of antigens (48,62,133); (ii) the glioma-induced immunosuppressive TME characterized by enrichment of microglia/macrophages and upregulated TGF-ß, IL-10, STAT3 and IDO/kynurenine (25,134–137); (iii) the anatomically and functionally restricted antigen presentation due to downregulated MHC expression, the presence of the BBB and the absence of intracranial regional lymph nodes (LNs) in the CNS (14,138,139); and (iv) a highly infiltrative growth pattern that makes it harder for therapeutic agents to traffic to (140,141). Some features are shared with BMs but others are not. Among them, it is our particular interest to shed more light on the issue of restricted antigen presentation in the CNS, and the difference of the TME between primary and metastatic brain tumors. Figure 1. Open in new tabDownload slide Cancer-immunity cycle and immune surveillance of CNS and non-CNS tumors. A. Cancer-Immunity Cycle. Source: Reprinted with permission from Elsevier. Chen DS and Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 2013. (142) B. Difference in afferent and efferent arm of immune-surveillance between CNS and non-CNS tumors, Source: Adapted from Galea et al. (138). LN, lymph node; APCs, antigen-presenting cells. Figure 1. Open in new tabDownload slide Cancer-immunity cycle and immune surveillance of CNS and non-CNS tumors. A. Cancer-Immunity Cycle. Source: Reprinted with permission from Elsevier. Chen DS and Mellman I. Oncology Meets Immunology: The Cancer-Immunity Cycle. Immunity 2013. (142) B. Difference in afferent and efferent arm of immune-surveillance between CNS and non-CNS tumors, Source: Adapted from Galea et al. (138). LN, lymph node; APCs, antigen-presenting cells. A restricted afferent arm of immune surveillance in the CNS When unique features of CNS immunity are discussed, the presence of the BBB often takes precedence as a restrictive entity. However, this is not always the case for T-cell migration across the BBB. To better understand the trafficking of T-cells throughout the CNS, we will use the cancer-immunity cycle (142) composed of seven key elements pertinent to the function and connectivity of the CNS (Fig. 1A). It is known that deep cervical LNs function as the primary draining LNs for intracranial lesions (relevant to element 3) (143–145). It is also appreciated that once ‘educated’, activated effector T-cells can traffic to the CNS and travel through the BBB (element 4 and 5) (146,147). There is accumulated evidence demonstrating antigen-specific T-cell migration and resultant tumor immunoediting in response (elements 6 and 7) (80,148). On the other hand, with respect to elements 1 and 2, the CNS parenchyma has highly isolated afferent communication with lymphatic systems owing to functional and anatomical restrictions (Fig. 1B). To overcome element 2 in the cancer-immune cycle, tumor antigens must be taken up by antigen-presenting cells (APCs), such as dendritic cells (DCs), macrophages and B cells, either inside or outside the tumor bed (149). For example, conventional DCs have been identified in the choroid plexus and meninges in animal models (139). However, it is uncertain whether beneficial antigen presentation occurs inside the glioma TME, even if a small number of DCs are present, because of the enriched population of tumor-associated, immunosuppressive, pro-tumorigenic microglia/macrophages (TAMs) as described later. When considering the modes of antigen presentation outside the tumor bed, it is crucial to understand the drainage routes of extracellular fluid in the CNS—interstitial fluid (ISF) and cerebrospinal fluid (CSF) (145). They drain into regional LNs via different routes, as reviewed in detail in the following references (14,147,150-152) (Fig. 2A). ISF and solute antigens drain from the parenchyma to cervical LNs along 100–150 nm wide arterial intramural perivascular spaces (Fig. 2B), as experimentally demonstrated both in animals and humans (153,154). Since this pathway is too narrow for APCs to migrate (154), they must rely on the CSF drainage route. Perivascular space surrounding postcapillary venules is connected with the CSF space consisting of the subarachnoid and intraventricular spaces (Fig. 2C). CSF can drain to the cervical LNs, mainly passing through the cribriform plate of the ethmoid bone to the nasal mucosa, or through the recently discovered peri-venous sinus dural lymphatics (Fig. 2A). However, there remain critical unanswered questions: which type of APCs play a leading role in antigen capture, where does this occur, and by what mechanism(s)? One possible explanation involves the intraventricular and subarachnoid spaces, where a small number of DCs are present. Nevertheless, the communication between ISF and CSF is strictly restricted by the ‘glymphatic system’, a perivascular channel system formed by astrocytic endfeet and basement membrane; only a tiny fraction of ISF (15%) is secreted into the CSF (14), and the role of the glymphatic system in this process still remains controversial (147,155). Another scenario focuses on macrophages localized in the perivascular space of the postcapillary venules (Fig. 2B). But their role in this context is still undetermined (156). Figure 2. Open in new tabDownload slide Neuroanatomical restriction of antigen presentation. A. Three main potential routes out of the intracranial diseases for antigen presentation at the deep cervical LN. ISF containing antigens can migrate through arterial perivascular space into the LN (shown in purple), but this space is too narrow for immune cells. In contrast, immune cells that are capable of capturing the antigens may reach to the LN using the CSF routes, either cribriform plate-nasal lymphatics, or peri-sinus dural lymphatics (shown in green). B. Perivascular space of postcapillary venules directly connected to the subarachnoid space. Extravasation of immune cells can take place at neither arteriole nor capillary but at postcapillary venule levels. Although ISF-CSF exchange is restricted by glia-limitans, it is thought that APCs in the CSF spaces, such as dendritic cells may play a key role in the tumor antigen capture. C. On the other hand, ISF containing the soluble antigens can drain at capillary levels and migrate within the arteriole perivascular space (tunica media) toward the LN, retrograde to blood flow. BBB, blood–brain barrier; BM, basement membrane; CSF, cerebrospinal fruid; ISF, interstitial fluid; SMC, smooth muscle cell. Source: Adapted from Engelhardt et al. (14) and Ratnam et al. (152). Figure 2. Open in new tabDownload slide Neuroanatomical restriction of antigen presentation. A. Three main potential routes out of the intracranial diseases for antigen presentation at the deep cervical LN. ISF containing antigens can migrate through arterial perivascular space into the LN (shown in purple), but this space is too narrow for immune cells. In contrast, immune cells that are capable of capturing the antigens may reach to the LN using the CSF routes, either cribriform plate-nasal lymphatics, or peri-sinus dural lymphatics (shown in green). B. Perivascular space of postcapillary venules directly connected to the subarachnoid space. Extravasation of immune cells can take place at neither arteriole nor capillary but at postcapillary venule levels. Although ISF-CSF exchange is restricted by glia-limitans, it is thought that APCs in the CSF spaces, such as dendritic cells may play a key role in the tumor antigen capture. C. On the other hand, ISF containing the soluble antigens can drain at capillary levels and migrate within the arteriole perivascular space (tunica media) toward the LN, retrograde to blood flow. BBB, blood–brain barrier; BM, basement membrane; CSF, cerebrospinal fruid; ISF, interstitial fluid; SMC, smooth muscle cell. Source: Adapted from Engelhardt et al. (14) and Ratnam et al. (152). Consequently, the afferent arm of immune surveillance, or element 2 in the cancer-immunity cycle, is highly restricted in the CNS; the adaptive immune response is hardly triggered spontaneously to the antigens of primary CNS tumors. On the other hand, such a conclusion is not applicable to the case of BMs since a more efficient antigen presentation is expected at the extracranial primary disease site (142,150,157). Hence, the contrasting clinical efficacy of ICIs for gliomas and BMs can be explained by the differences in magnitude and range of antigen presentation in either case. Currently, many of the immunotherapies in development, such as vaccines and immune cell therapies, are designed to bypass the issue of poor antigen presentation in a more targeted fashion. Difference in TME The TME is comprised of cancer cells as well as many different noncancerous cell types, such as endothelial cells, fibroblasts and immune cells. In addition, tissue-resident cell types in the CNS, such as microglia, astrocytes and neurons contribute to the formulation of an immunosuppressive environment (36,158). It is well acknowledged that ~30–50% of cellular components in the TME of GBM are comprised of myeloid cells, such as microglia, macrophages and myeloid-derived suppressor cells (MDSCs) (25). In particular, immunosuppressive ‘M2’ TAMs are recruited by CSF-1 secreted by glioma cells (159), and lack the costimulatory molecules CD80, CD86 and CD40 essential for T-cell activation (160). In addition, secretion of IL-10 and TGF-ß by these M2-TAMs not only downregulates the expression of MHC class-II on glioma and myeloid cells, but also suppresses DC maturation (161,162), provoking defects in the antigen-presenting machinery (25,134). Moreover, beyond the organ specificity, disease-specific genetic alterations, such as IDH1 mutation (53,54,163), NF1 loss (46) and N-Myc amplification (164), can all contribute to local immunosuppression. Furthermore, two separate studies recently dissected the disease-specific features of the TME with high-resolution analyses (165,166). Friebel et al. (165) conducted a mass cytometry-based single-cell analysis of surgically resected brain tumors and non-tumor controls from 38 patients. Concordantly with the other study, they found TAMs dominated the TME in gliomas (~80% of leukocytes) whereas lymphocytes dominated in BMs (~50%). Of note, glioma predominantly harbored TAMs of microglial origin, whereas BMs were highly invaded by a higher number of monocyte-derived macrophages (MDMs). Interestingly, macrophage composition was very similar between IDH-mutant gliomas and non-tumor brain tissue. By analyzing the developmental trajectory of monocyte-to-MDM transition, the researchers clarified that even the composition of MDMs was distinct among diseases. In addition, regarding T-cells, the glioma TME was characterized by lower expression of activation markers whereas the metastatic TME was composed of activated/exhausted T-cells. Klemm et al. (166) also investigated the difference of the TME among non-tumor brain tissue, IDH-mutant and wild-type gliomas, as well as several types of BMs using flow-cytometry, immunofluorescence (IF), RNA-sequencing (RNAseq) and spatial tissue characterization. Within CD45+ cells in clinical tumor specimens, a significant enrichment in myeloid cells was observed in gliomas regardless of IDH status, while the abundance of lymphoid lineage cells was significantly higher in IDH-wild-type gliomas and BMs. RNA-seq analyses demonstrated that a substantially higher proportion of lymphocytes with the most diverse landscape was observed in BMs, especially those originating from melanoma. Interestingly, the lymphocyte composition also varied among BMs of different origins; for example, T cells were dominant in melanoma BMs, whereas breast cancer BMs were characterized by the highest neutrophil infiltration. In addition, the analysis on the spatial relationship of TILs using IF-phenotyped tissue sections revealed that both TAM populations resided close to T cells more frequently in BMs, suggesting their interaction. By contrast, in IDH-wild-type gliomas, tumor-associated microglia and MDMs lacked T cells in their close vicinity. In summary, both studies consistently demonstrated that immune cell composition and their respective phenotypic and functional features are dependent on the disease type, instead of the CNS tissue environment itself. It is reasonable that the difference of ICI efficacy may be, at least in part, explained by such a difference of the TME. In addition, although encouraging data have been reported for treatment of melanoma and lung cancer BMs with ICIs so far, their efficacy may not be uniform among BMs originating from other cancer types with different TME compositions. Concluding remarks As discussed, although no established, effective immunotherapy has been developed for glioma thus far, several promising approaches have been proposed in the last few years, such as neoadjuvant ICIs, personalized multipeptide vaccines, CAR-T therapies and virus-based immunotherapies. In addition, accumulated data has demonstrated that ICIs can be an effective treatment option for some types of BMs. Although the CNS can no longer be considered completely immune-privileged, this does not lighten the remaining challenges immunotherapeutic modalities must overcome, especially in encountering restricted antigen presentation and the immunosuppressive TME. This has been partially reflected in the differences in TIL composition and ICI efficacy between primary and secondary brain tumors. Better understanding of these unique immunological characteristics of the CNS as well as thoughtful design of combinatorial therapeutic modalities will be required for future success in immunotherapy for both primary and secondary tumors. Funding Support NIH/NINDS 1R35 NS105068 (HO) Conflict of interest statement Hideho Okada is an inventor of the following US utility patent applications; ‘H3.3 CTL peptides and uses thereof’ (Case Number, SF2015–163), which has been exclusively licensed to Tmunity, Inc., ‘Anti-EGFRvIII chimeric antigen receptor (Case Number , U Penn 02980), which has been exclusively licensed to Novartis Pharma, Inc. and ‘Identification of an IL-13 Receptor Alpha2 Peptide Analogue Capable of Enhancing Stimulation of Glioma-Specific CTL Response’, which has been exclusively licensed to Stemline, Inc. Takahide Nejo received scholarship from TOYOBO biotechnology foundation (2019–2020). References 1. Stewart BW , Wild C. International Agency for Research on Cancer, World Health Organization. In: World Cancer Report 2014: International Agency for Research on Cancer . WHO Press , 2014 ; 630 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 2. Ostrom QT , Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012–2016 . 21 . Neuro Oncol , 2019 ; v1 – v100 . 3. Sanai N , Chang S, Berger MS. Low-grade gliomas in adults . J Neurosurg 2011 ; 115 : 948 – 65 . doi: 10.3171/2011.7.JNS101238 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Brain Tumor Progress Review Group . National Institute of Neurological Disorders and Stroke (U.S.), National Cancer Institute (U.S.). Report of the Brain Tumor Progress Review Group. Bethesda, Md . National Institute of Neurological Disorders and Stroke: National Cancer Institute , 2000 ; 96 . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 5. Schroeder KM , Hoeman CM, Becher OJ. Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology . Pediatr Res 2014 ; 75 : 205 – 9 . doi: 10.1038/pr.2013.194 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Kebudi R , Cakir FB. Management of diffuse pontine gliomas in children: recent developments . Paediatr Drugs 2013 ; 15 : 351 – 62 . doi: 10.1007/s40272-013-0033-5 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Lin X , DeAngelis LM. Treatment of brain metastases . J Clin Oncol 2015 ; 33 : 3475 – 84 . doi: 10.1200/JCO.2015.60.9503 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Nayak L , Lee EQ, Wen PY. Epidemiology of brain metastases . Curr Oncol Rep 2012 ; 14 ( 1 ): 48 – 54 . doi: 10.1007/s11912-011-0203-y . Google Scholar Crossref Search ADS PubMed WorldCat 9. Cagney DN , Martin AM, Catalano PJ, Redig AJ, Lin NU, Lee EQ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: a population-based study . Neuro Oncol 2017 ; 19 : 1511 – 21 . doi: 10.1093/neuonc/nox077 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Fox BD , Cheung VJ, Patel AJ, Suki D, Rao G. Epidemiology of metastatic brain tumors . Neurosurg Clin N Am 2011 ; 22 : 1 – 6 v . doi: 10.1016/j.nec.2010.08.007 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Ascha MS , Ostrom QT, Wright J, Kumthekar P, Bordeaux JS, Sloan AE, et al. Lifetime occurrence of brain metastases arising from lung, breast, and skin cancers in the elderly: a SEER-Medicare study . Cancer Epidemiol Biomarkers Prev 2019 ; 28 : 917 – 25 . doi: 10.1158/1055-9965 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Di Giacomo AM , Valente M, Cerase A, Lofiego MF, Piazzini F, Calabrò L, et al. Immunotherapy of brain metastases: breaking a "dogma" . J Exp Clin Cancer Res 2019 ; 38 : 419 . doi: 10.1186/s13046-019-1426-2 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Kavouridis VK , Harary M, Hulsbergen AFC, Lo YT, Reardon DA, Aizer AA, et al. Survival and prognostic factors in surgically treated brain metastases . J Neurooncol 2019 ; 143 : 359 – 67 . doi: 10.1007/s11060-019-03171-6 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Engelhardt B , Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS . Nat Immunol 2017 ; 18 : 123 – 31 . doi: 10.1038/ni.3666 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Aspelund A , Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules . J Exp Med 2015 ; 212 : 991 – 9 . doi: 10.1084/jem.20142290 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Hodi FS , O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma . N Engl J Med 2010 ; 363 : 711 – 23 . doi: 10.1056/NEJMoa1003466 . Google Scholar Crossref Search ADS PubMed WorldCat 17. Goldberg S , Gettinger S, Mahajan A, Herbst R, Chiang A, Lilenbaum R, et al. Durability of brain metastasis response and overall survival in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab . J Clin Oncol 2018 ; 36 : 2009 . doi: 10.1200/JCO.2018.36.15_suppl.2009 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Tawbi H-H , Forsyth P, Algazi A, Hamid O, Hodi F, Moschos S, et al. Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: results of the phase II study CheckMate 204 . J Clin Oncol 2017 ; 35 . doi: 10.1200/JCO.2017.35.15_suppl.9507 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 19. Reardon DA , Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of nivolumab vs Bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial . JAMA Oncol 2020 ; 6 : 1–8 . doi: 10.1001/jamaoncol.2020.1024 . Google Scholar Crossref Search ADS WorldCat 20. Weller M , Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial . Lancet Oncol 2017 ; 18 : 1373 – 85 . doi: 10.1016/S1470-2045(17)30517-X . Google Scholar Crossref Search ADS PubMed WorldCat 21. Chuntova P , Downey KM, Hegde B, Almeida ND, Okada H. Genetically engineered T-cells for malignant Glioma: overcoming the barriers to effective immunotherapy . Front Immunol 2018 ; 9 : 3062 . doi: 10.3389/fimmu.2018.03062 . Google Scholar Crossref Search ADS PubMed WorldCat 22. Kwok D , Okada H. T-cell based therapies for overcoming neuroanatomical and immunosuppressive challenges within the glioma microenvironment . J Neurooncol 2020 ; 147 : 281 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Lin Y , Okada H. Cellular immunotherapy for malignant gliomas . Expert Opin Biol Ther 2016 ; 16 : 1265 – 75 . doi: 10.1080/14712598.2016.1214266 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Nejo T , Yamamichi A, Almeida ND, Goretsky YE, Okada H. Tumor antigens in glioma . Semin Immunol 2020 ; 47 : 101385 . doi: 10.1016/j.smim.2020.101385 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Buerki RA , Chheda ZS, Okada H. Immunotherapy of primary brain Tumors: facts and hopes . Clin Cancer Res 2018 ; 24 : 5198–205 . doi: 10.1158/1078-0432.CCR-17-2769 . Google Scholar Crossref Search ADS WorldCat 26. Lim M , Xia Y, Bettegowda C, Weller M. Current state of immunotherapy for glioblastoma . Nat Rev Clin Oncol 2018 ; 15 : 422 – 42 . doi: 10.1038/s41571-018-0003-5 . Google Scholar Crossref Search ADS PubMed WorldCat 27. Fecci PE , Sampson JH. The current state of immunotherapy for gliomas: an eye toward the future . J Neurosurg 2019 ; 131 : 657 – 66 . doi: 10.3171/2019.5.JNS181762 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Sampson JH , Gunn MD, Fecci PE, Ashley DM. Brain immunology and immunotherapy in brain tumours . Nat Rev Cancer 2020 ; 20 : 12 – 25 . doi: 10.1038/s41568-019-0224-7 . Google Scholar Crossref Search ADS PubMed WorldCat 29. Rizvi NA , Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer . Science 2015 ; 348 : 124 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 30. Snyder A , Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma . N Engl J Med 2014 ; 371 : 2189 – 99 . doi: 10.1056/NEJMoa1406498 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Le DT , Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in Tumors with mismatch-repair deficiency . N Engl J Med 2015 ; 372 : 2509 – 20 . doi: 10.1056/NEJMoa1500596 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Motzer RJ , Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma . N Engl J Med 2015 ; 373 : 1803 – 13 . doi: 10.1056/NEJMoa1510665 . Google Scholar Crossref Search ADS PubMed WorldCat 33. Wolchok JD , Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma . N Engl J Med 2017 ; 377 : 1345 – 56 . doi: 10.1056/NEJMoa1709684 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Bristol-Myers Squibb . Opdivo (nivolumab) [prescribing information]. https://docs.google.com/viewer?url=https%3A%2F%2Fpackageinserts.bms.com%2Fpi%2Fpi_opdivo.pdf. ( 8 May 2020, date last accessed ). 35. Banks WA . Characteristics of compounds that cross the blood-brain barrier . BMC Neurol 2009 ; 9 : S3 . doi: 10.1186/1471-2377-9-S1-S3 . Google Scholar Crossref Search ADS PubMed WorldCat 36. Quail DF , Joyce JA. The microenvironmental landscape of brain Tumors . Cancer Cell 2017 ; 31 : 326 – 41 . doi: 10.1016/j.ccell.2017.02.009 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Reardon DA , Gokhale PC, Klein SR, Ligon KL, Rodig SJ, Ramkissoon SH, et al. Glioblastoma eradication following immune checkpoint blockade in an Orthotopic . Immunocompetent Model Cancer Immunol Res 2016 ; 4 : 124 – 35 . doi: 10.1158/2326-6066.CIR-15-0151 . Google Scholar Crossref Search ADS PubMed WorldCat 38. Wainwright DA , Chang AL, Dey M, Balyasnikova IV, Kim CK, Tobias A, et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors . Clin Cancer Res 2014 ; 20 : 5290 – 301 . Google Scholar Crossref Search ADS PubMed WorldCat 39. Omuro A , Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143 . Neuro Oncol 2018 ; 20 : 674 – 86 . doi: 10.1093/neuonc/nox208 . Google Scholar Crossref Search ADS PubMed WorldCat 40. Bristol-Myers Squibb . Press release: Bristol-Myers Squibb Announces Phase 3 CheckMate −498 Study Did Not Meet Primary Endpoint of Overall Survival with Opdivo (nivolumab) Plus Radiation in Patients with Newly Diagnosed MGMT-Unmethylated Glioblastoma Multiforme 2019 . https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-announces-phase-3-checkmate-498-study-did%20 ( 8 May 2020, date last accessed ). 41. Bristol-Myers Squibb. Press Release: Bristol-Myers Squibb Provides Update on Phase 3 Opdivo (nivolumab) CheckMate −548 Trial in Patients with Newly Diagnosed MGMT-Methylated Glioblastoma Multiforme 2019 . https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-provides-update-phase-3-opdivo-nivolumab- (8 May 2020, date last accessed). 42. Zhao J , Chen AX, Gartrell RD, Silverman AM, Aparicio L, Chu T, et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma . Nat Med 2019 ; 25 : 462 – 9 . doi: 10.1038/s41591-019-0349-y . Google Scholar Crossref Search ADS PubMed WorldCat 43. Cloughesy TF , Mochizuki AY, Orpilla JR, Hugo W, Lee AH, Davidson TB, et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma . Nat Med 2019 ; 25 : 477 – 86 . doi: 10.1038/s41591-018-0337-7 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Schalper KA , Rodriguez-Ruiz ME, Diez-Valle R, López-Janeiro A, Porciuncula A, Idoate MA, et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma . Nat Med 2019 ; 25 : 470 – 6 . doi: 10.1038/s41591-018-0339-5 . Google Scholar Crossref Search ADS PubMed WorldCat 45. Filley AC , Henriquez M, Dey M. Recurrent glioma clinical trial, CheckMate-143: the game is not over yet . Oncotarget 2017 ; 8 : 91779 – 94 . doi: 10.18632/oncotarget.21586 . Google Scholar Crossref Search ADS PubMed WorldCat 46. Wang Q , Hu B, Hu X, Kim H, Squatrito M, Scarpace L, et al. Tumor evolution of Glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment . Cancer Cell 2017 ; 32 : 42 – 56.e6 . doi: 10.1016/j.ccell.2017.06.003 . Google Scholar Crossref Search ADS PubMed WorldCat 47. Touat M , Li YY, Boynton AN, Spurr LF, Iorgulescu JB, Bohrson CL, et al. Mechanisms and therapeutic implications of hypermutation in gliomas . Nature 2020 ; 580 : 517 – 23 . doi: 10.1038/s41586-020-2209-9 . Google Scholar Crossref Search ADS PubMed WorldCat 48. Wang J , Cazzato E, Ladewig E, Frattini V, Rosenbloom DI, Zairis S, et al. Clonal evolution of glioblastoma under therapy . Nat Genet 2016 ; 48 : 768 – 76 . doi: 10.1038/ng.3590 . Google Scholar Crossref Search ADS PubMed WorldCat 49. Yarchoan M , Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition . N Engl J Med 2017 ; 377 : 2500 – 1 . doi: 10.1056/NEJMc1713444 . Google Scholar Crossref Search ADS PubMed WorldCat 50. Bouffet E , Larouche V, Campbell BB, Merico D, de Borja R, Aronson M, et al. Immune checkpoint inhibition for Hypermutant glioblastoma Multiforme resulting from Germline Biallelic mismatch repair deficiency . J Clin Oncol 2016 ; 34 : 2206 – 11 . doi: 10.1200/JCO.2016.66.6552 . Google Scholar Crossref Search ADS PubMed WorldCat 51. Johanns TM , Miller CA, Dorward IG, Tsien C, Chang E, Perry A, et al. Immunogenomics of Hypermutated glioblastoma: a patient with Germline POLE deficiency treated with checkpoint blockade immunotherapy . Cancer Discov 2016 ; 6 : 1230 – 6 . doi: 10.1158/2159-8290.CD-16-0575 . Google Scholar Crossref Search ADS PubMed WorldCat 52. Ahmad H , Fadul CE, Schiff D, Purow B. Checkpoint inhibitor failure in hypermutated and mismatch repair-mutated recurrent high-grade gliomas . Neurooncol Pract 2019 ; 6 : 424 – 7 . doi: 10.1093/nop/npz016 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 53. Kohanbash G , Carrera DA, Shrivastav S, Ahn BJ, Jahan N, Mazor T, et al. Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas . J Clin Invest 2017 ; 127 : 1425 – 37 . doi: 10.1172/JCI90644 . Google Scholar Crossref Search ADS PubMed WorldCat 54. Bunse L , Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate . Nat Med 2018 ; 24 ( 8 ): 1192 – 203 . doi: 10.1038/s41591-018-0095-6 . Google Scholar Crossref Search ADS PubMed WorldCat 55. Amankulor NM , Kim Y, Arora S, Kargl J, Szulzewsky F, Hanke M, et al. Mutant IDH1 regulates the tumor-associated immune system in gliomas . Genes Dev 2017 ; 31 : 774 – 86 . doi: 10.1101/gad.294991.116 . Google Scholar Crossref Search ADS PubMed WorldCat 56. Choi S , Yu Y, Grimmer MR, Wahl M, Chang SM, Costello JF. Temozolomide-associated hypermutation in gliomas . Neuro Oncol 2018 ; 20 : 1300 – 9 . doi: 10.1093/neuonc/noy016 . Google Scholar Crossref Search ADS PubMed WorldCat 57. Topalian SL , Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy . Science 2020 ; 367 . doi: 10.1126/science.aax0182 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 58. Berghoff AS , Preusser M. Does neoadjuvant anti-PD1 therapy improve glioblastoma outcome? Nat Rev Neurol 2019 ; 15 : 314 – 5 . doi: 10.1038/s41582-019-0178-0 . Google Scholar Crossref Search ADS PubMed WorldCat 59. Weller M , Roth P, Preusser M, Wick W, Reardon DA, Platten M, et al. Vaccine-based immunotherapeutic approaches to gliomas and beyond . Nat Rev Neurol 2017 ; 13 : 363 – 74 . doi: 10.1038/nrneurol.2017.64 . Google Scholar Crossref Search ADS PubMed WorldCat 60. Sampson JH , Heimberger AB, Archer GE, Aldape KD, Friedman AH, Friedman HS, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma . J Clin Oncol 2010 ; 28 : 4722 – 9 . doi: 10.1200/JCO.2010.28.6963 . Google Scholar Crossref Search ADS PubMed WorldCat 61. Reardon DA , Desjardins A, Vredenburgh JJ, O'Rourke DM, Tran DD, Fink KL, et al. Rindopepimut with Bevacizumab for patients with relapsed EGFRvIII-expressing glioblastoma (ReACT): results of a double-blind randomized phase II trial . Clin Cancer Res 2020 ; 26 : 1586 – 94 . doi: 10.1158/1078-0432.CCR-18-1140 . Google Scholar Crossref Search ADS PubMed WorldCat 62. Nejo T , Matsushita H, Karasaki T, Nomura M, Saito K, Tanaka S, et al. Reduced Neoantigen expression revealed by longitudinal Multiomics as a possible immune evasion mechanism in Glioma . Cancer Immunol Res 2019 ; 7 : 1148 – 61 . doi: 10.1158/2326-6066.CIR-18-0599 . Google Scholar Crossref Search ADS PubMed WorldCat 63. Rosenthal R , Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, et al. Neoantigen-directed immune escape in lung cancer evolution . Nature 2019 ; 567 : 479 – 85 . doi: 10.1038/s41586-019-1032-7 . Google Scholar Crossref Search ADS PubMed WorldCat 64. Solomon DA , Wood MD, Tihan T, Bollen AW, Gupta N, Phillips JJ, et al. Diffuse midline Gliomas with histone H3-K27M mutation: a series of 47 cases assessing the Spectrum of morphologic variation and associated genetic alterations . Brain Pathol 2016 ; 26 : 569 – 80 . doi: 10.1111/bpa.12336 . Google Scholar Crossref Search ADS PubMed WorldCat 65. Mazor T , Chesnelong C, Pankov A, Jalbert LE, Hong C, Hayes J, et al. Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1 . Proc Natl Acad Sci U S A 2017 ; 114 : 10743 – 8 . doi: 10.1073/pnas.1708914114 . Google Scholar Crossref Search ADS PubMed WorldCat 66. Schumacher T , Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity . Nature 2014 ; 512 : 324 – 7 . doi: 10.1038/nature13387 . Google Scholar Crossref Search ADS PubMed WorldCat 67. Platten M , Schilling D, Bunse L, Wick A, Bunse T, Riehl D, et al. ATIM-33. NOA-16: a first-in-man multicenter phase I clinical trial of the German Neurooncology working group evaluating a mutation-specific peptide vaccine targeting IDH1R132H in patients with newly diagnosed malignant ASTROCYTOMAS . Neuro Oncol 2018 ; 20 : vi8 – 9 . doi: 10.1093/neuonc/noy148.028 . Google Scholar Crossref Search ADS WorldCat 68. Ochs K , Ott M, Bunse T, Sahm F, Bunse L, Deumelandt K, et al. K27M-mutant histone-3 as a novel target for glioma immunotherapy . Onco Targets Ther 2017 ; 6 : e1328340 . doi: 10.1080/2162402X.2017.1328340 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 69. Chheda ZS , Kohanbash G, Okada K, Jahan N, Sidney J, Pecoraro M, et al. Novel and shared neoantigen derived from histone 3 variant H3.3K27M mutation for glioma T cell therapy . J Exp Med 2018 ; 215 : 141 – 57 . doi: 10.1084/jem.20171046 . Google Scholar Crossref Search ADS PubMed WorldCat 70. Mueller S , Lulla R, Goldman S, Banerjee A, Chi S, Whipple N, et al. PDCT-17 (LTBK-11). PNOC007: H3.3K27M specific peptide vaccine combined with poly-ICLC for the treatment of newly diagnosed HLA-A2+ H3.3K27M midline GLIOMAS . Neuro Oncol 2019 ; 21 : vi284 – vi5 . doi: 10.1093/neuonc/noz219.1200 . Google Scholar Crossref Search ADS WorldCat 71. Mueller S , Taitt JM, Villanueva-Meyer JE, Bonner ER, Nejo T, Lulla RR, et al. Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma . Clin Invest . 2020 Aug 20: 140378 . doi: 10.1172/JCI140378 . Online ahead of print. Google Scholar OpenURL Placeholder Text WorldCat Crossref 72. Dutoit V , Migliorini D, Ranzanici G, Marinari E, Widmer V, Lobrinus JA, et al. Antigenic expression and spontaneous immune responses support the use of a selected peptide set from the IMA950 glioblastoma vaccine for immunotherapy of grade II and III glioma . Onco Targets Ther 2018 ; 7 : e1391972 . doi: 10.1080/2162402X.2017.1391972 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 73. Rampling R , Peoples S, Mulholland PJ, James A, Al-Salihi O, Twelves CJ, et al. A Cancer Research UK first time in human phase I trial of IMA950 (novel multipeptide therapeutic vaccine) in patients with newly diagnosed glioblastoma . Clin Cancer Res 2016 ; 22 : 4776 – 85 . doi: 10.1158/1078-0432 . Google Scholar Crossref Search ADS PubMed WorldCat 74. Migliorini D , Dutoit V, Allard M, Grandjean Hallez N, Marinari E, Widmer V, et al. Phase I/II trial testing safety and immunogenicity of the multipeptide IMA950/poly-ICLC vaccine in newly diagnosed adult malignant astrocytoma patients . Neuro Oncol 2019 ; 21 : 923 – 33 . doi: 10.1093/neuonc/noz040 . Google Scholar Crossref Search ADS PubMed WorldCat 75. Narita Y , Arakawa Y, Yamasaki F, Nishikawa R, Aoki T, Kanamori M, et al. A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma . Neuro Oncol 2019 ; 21 : 348 – 59 . doi: 10.1093/neuonc/noy200 . Google Scholar Crossref Search ADS PubMed WorldCat 76. Terasaki M , Shibui S, Narita Y, Fujimaki T, Aoki T, Kajiwara K, et al. Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen--A24 with recurrent or progressive glioblastoma multiforme . J Clin Oncol 2011 ; 29 : 337 – 44 . doi: 10.1200/JCO.2010.29.7499 . Google Scholar Crossref Search ADS PubMed WorldCat 77. Hilf N , Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, et al. Actively personalized vaccination trial for newly diagnosed glioblastoma . Nature 2019 ; 565 : 240 – 5 . doi: 10.1038/s41586-018-0810-y . Google Scholar Crossref Search ADS PubMed WorldCat 78. Zhu X , Nishimura F, Sasaki K, Fujita M, Dusak JE, Eguchi J, et al. Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models . J Transl Med 2007 ; 5 : 10 . doi: 10.1186/1479-5876-5-10 . Google Scholar Crossref Search ADS PubMed WorldCat 79. Dutoit V , Herold-Mende C, Hilf N, Schoor O, Beckhove P, Bucher J, et al. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy . Brain 2012 ; 135 : 1042 – 54 . doi: 10.1093/brain/aws042 . Google Scholar Crossref Search ADS PubMed WorldCat 80. Keskin DB , Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial . Nature 2019 ; 565 : 234 – 9 . doi: 10.1038/s41586-018-0792-9 . Google Scholar Crossref Search ADS PubMed WorldCat 81. Rosenberg SA , Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer . Science 2015 ; 348 : 62 – 8 . doi: 10.1126/science.aaa4967 . Google Scholar Crossref Search ADS PubMed WorldCat 82. Quattrocchi KB , Miller CH, Cush S, Bernard SA, Dull ST, Smith M, et al. Pilot study of local autologous tumor infiltrating lymphocytes for the treatment of recurrent malignant gliomas . J Neurooncol 1999 ; 45 : 141 – 57 . doi: 10.1023/a:1006293606710 . Google Scholar Crossref Search ADS PubMed WorldCat 83. Saris SC , Spiess P, Lieberman DM, Lin S, Walbridge S, Oldfield EH. Treatment of murine primary brain tumors with systemic interleukin-2 and tumor-infiltrating lymphocytes . J Neurosurg 1992 ; 76 : 513 – 9 . doi: 10.3171/jns.1992.76.3.0513 . Google Scholar Crossref Search ADS PubMed WorldCat 84. Kahlon KS , Brown C, Cooper LJ, Raubitschek A, Forman SJ, Jensen MC. Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells . Cancer Res 2004 ; 64 : 9160 – 6 . doi: 10.1158/0008-5472.CAN-04-0454 . Google Scholar Crossref Search ADS PubMed WorldCat 85. Ahmed N , Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, et al. HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors . Clin Cancer Res 2010 ; 16 : 474 – 85 . doi: 10.1158/1078-0432.CCR-09-1322 . Google Scholar Crossref Search ADS PubMed WorldCat 86. Chow KK , Naik S, Kakarla S, Brawley VS, Shaffer DR, Yi Z, et al. T cells redirected to EphA2 for the immunotherapy of glioblastoma . Mol Ther 2013 ; 21 : 629 – 37 . doi: 10.1038/mt.2012.210 . Google Scholar Crossref Search ADS PubMed WorldCat 87. Johnson LA , Scholler J, Ohkuri T, Kosaka A, Patel PR, McGettigan SE, et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma . Sci Transl Med 2015 ; 7 : 275ra22 . doi: 10.1126/scitranslmed.aaa4963 . Google Scholar Crossref Search ADS PubMed WorldCat 88. Brown CE , Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy . N Engl J Med 2016 ; 375 : 2561 – 9 . doi: 10.1056/NEJMoa1610497 . Google Scholar Crossref Search ADS PubMed WorldCat 89. Rossig C , Kailayangiri S, Jamitzky S, Altvater B. Carbohydrate targets for CAR T cells in solid childhood cancers . Front Oncol 2018 ; 8 : 513 . doi: 10.3389/fonc.2018.00513 . Google Scholar Crossref Search ADS PubMed WorldCat 90. Cahan LD , Irie RF, Singh R, Cassidenti A, Paulson JC. Identification of a human neuroectodermal tumor antigen (OFA-I-2) as ganglioside GD2 . Proc Natl Acad Sci U S A 1982 ; 79 : 7629 – 33 . doi: 10.1073/pnas.79.24.7629 . Google Scholar Crossref Search ADS PubMed WorldCat 91. Schulz G , Cheresh DA, Varki NM, Yu A, Staffileno LK, Reisfeld RA. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients . Cancer Res 1984 ; 44 : 5914 – 20 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 92. Cheung NK , Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, et al. Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma . J Clin Oncol 1987 ; 5 : 1430 – 40 . doi: 10.1200/JCO.1987.5.9.1430 . Google Scholar Crossref Search ADS PubMed WorldCat 93. Rossig C , Bollard CM, Nuchtern JG, Merchant DA, Brenner MK. Targeting of G(D2)-positive tumor cells by human T lymphocytes engineered to express chimeric T-cell receptor genes . Int J Cancer 2001 ; 94 : 228 – 36 . doi: 10.1002/ijc.1457 . Google Scholar Crossref Search ADS PubMed WorldCat 94. Rossig C , Bollard CM, Nuchtern JG, Rooney CM, Brenner MK. Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy . Blood 2002 ; 99 : 2009 – 16 . doi: 10.1182/blood.v99.6.2009 . Google Scholar Crossref Search ADS PubMed WorldCat 95. Louis CU , Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma . Blood 2011 ; 118 : 6050 – 6 . doi: 10.1182/blood-2011-05-354449 . Google Scholar Crossref Search ADS PubMed WorldCat 96. Pule MA , Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma . Nat Med 2008 ; 14 : 1264 – 70 . doi: 10.1038/nm.1882 . Google Scholar Crossref Search ADS PubMed WorldCat 97. Mount CW , Majzner RG, Sundaresh S, Arnold EP, Kadapakkam M, Haile S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M . Nat Med 2018 ; 24 : 572 – 9 . doi: 10.1038/s41591-018-0006-x . Google Scholar Crossref Search ADS PubMed WorldCat 98. Okada H , Noriyuki K, Tumors B. In: Butterfield LH, Kaufman HL, Marincola FM, editor. Cancer Immunotherapy Principles and Practice . New York : Demos Medical Publishing , 2017 ; xxiii 893 pages . Google Scholar Google Preview OpenURL Placeholder Text WorldCat COPAC 99. Martikainen M , Essand M. Virus-based immunotherapy of glioblastoma . Cancers (Basel) 2019 ; 11 . doi: 10.3390/cancers11020186 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 100. Ahluwalia M , Hubben A, Desai K. Combination of oncolytic viruses and immune checkpoint inhibitors in glioblastoma . Glioma 2019 ; 2 : 7 . doi: 10.4103/glioma.glioma_5_19 . Google Scholar Crossref Search ADS WorldCat 101. Fueyo J , Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P, et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo . Oncogene 2000 ; 19 : 2 – 12 . doi: 10.1038/sj.onc.1203251 . Google Scholar Crossref Search ADS PubMed WorldCat 102. Lang FF , Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, et al. Phase I study of DNX-2401 (Delta-24-RGD) Oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant Glioma . J Clin Oncol 2018 ; 36 : 1419 – 27 . doi: 10.1200/JCO.2017.75.8219 . Google Scholar Crossref Search ADS PubMed WorldCat 103. Zadeh G , Lang F, Daras M, Cloughesy T, Colman H, Ong S, et al. ATIM-24. Interim results of a phase ii MULTICENTER study of the conditionally replicative ONCOLYTIC adenovirus DNX-2401 with PEMBROLIZUMAB (KEYTRUDA) for recurrent GLIOBLASTOMA; captive study (KEYNOTE-192) . Neuro Oncol 2018 ; 20 : vi6 . doi: 10.1093/neuonc/noy148.019 . Google Scholar Crossref Search ADS WorldCat 104. Yong RL , Shinojima N, Fueyo J, Gumin J, Vecil GG, Marini FC, et al. Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas . Cancer Res 2009 ; 69 : 8932 – 40 . doi: 10.1158/0008-5472.CAN-08-3873 . Google Scholar Crossref Search ADS PubMed WorldCat 105. Kim CK , Ahmed AU, Auffinger B, Ulasov IV, Tobias AL, Moon KS, et al. N-acetylcysteine amide augments the therapeutic effect of neural stem cell-based antiglioma oncolytic virotherapy . Mol Ther 2013 ; 21 : 2063 – 73 . doi: 10.1038/mt.2013.179 . Google Scholar Crossref Search ADS PubMed WorldCat 106. Martínez-Vélez N , Garcia-Moure M, Marigil M, González-Huarriz M, Puigdelloses M, Gallego Pérez-Larraya J, et al. The oncolytic virus Delta-24-RGD elicits an antitumor effect in pediatric glioma and DIPG mouse models . Nat Commun 2019 ; 10 : 2235 . doi: 10.1038/s41467-019-10043-0 . Google Scholar Crossref Search ADS PubMed WorldCat 107. Martinez-Velez N , Marigil M, Garcia-Moure M, Gonzalez-Huarriz M, Aristu JJ, Ramos-Garcia LI, et al. Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models . Acta Neuropathol Commun 2019 ; 7 : 64 . doi: 10.1186/s40478-019-0714-6 . Google Scholar Crossref Search ADS PubMed WorldCat 108. Jiang H , Rivera-Molina Y, Gomez-Manzano C, Clise-Dwyer K, Bover L, Vence LM, et al. Oncolytic adenovirus and tumor-targeting immune modulatory therapy improve autologous cancer vaccination . Cancer Res 2017 ; 77 : 3894 – 907 . doi: 10.1158/0008-5472.CAN-17-0468 . Google Scholar Crossref Search ADS PubMed WorldCat 109. Mineta T , Rabkin SD, Yazaki T, Hunter WD, Martuza RL. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas . Nat Med 1995 ; 1 : 938 – 43 . doi: 10.1038/nm0995-938 . Google Scholar Crossref Search ADS PubMed WorldCat 110. Markert JM , Medlock MD, Rabkin SD, Gillespie GY, Todo T, Hunter WD, et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial . Gene Ther 2000 ; 7 : 867 – 74 . doi: 10.1038/sj.gt.3301205 . Google Scholar Crossref Search ADS PubMed WorldCat 111. Markert JM , Liechty PG, Wang W, Gaston S, Braz E, Karrasch M, et al. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM . Mol Ther 2009 ; 17 : 199 – 207 . doi: 10.1038/mt.2008.228 . Google Scholar Crossref Search ADS PubMed WorldCat 112. Ring E , Moore B, Nan L, Etminan T, Markert J, Gillespie GY, et al. PCM-09 comparison of the sensitivities of PEDIATRIC high-grade BRAIN tumor versus adult GLIOBLASTOMA XENOGRAFTS to engineered ONCOLYTIC herpes simplex VIROTHERAPY . Neuro Oncol 2016 ; 18 : iii141 . doi: 10.1093/neuonc/now080.09 . Google Scholar Crossref Search ADS WorldCat 113. Waters AM , Johnston JM, Reddy AT, Fiveash J, Madan-Swain A, Kachurak K, et al. Rationale and Design of a Phase 1 clinical trial to evaluate HSV G207 alone or with a single radiation dose in children with progressive or recurrent malignant Supratentorial brain Tumors . Hum Gene Ther Clin Dev 2017 ; 28 : 7 – 16 . doi: 10.1089/humc.2017.002 . Google Scholar Crossref Search ADS PubMed WorldCat 114. Todo T , Martuza RL, Rabkin SD, Johnson PA. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing . Proc Natl Acad Sci U S A 2001 ; 98 : 6396 – 401 . doi: 10.1073/pnas.101136398 . Google Scholar Crossref Search ADS PubMed WorldCat 115. Todo T . ATIM-14. Results of phase ii clinical trial of ONCOLYTIC herpes virus G47Δ in patients with GLIOBLASTOMA . Neuro Oncol 2019 ; 21 : vi4 . doi: 10.1093/neuonc/noz175.014 . Google Scholar Crossref Search ADS WorldCat 116. Perez OD , Logg CR, Hiraoka K, Diago O, Burnett R, Inagaki A, et al. Design and selection of Toca 511 for clinical use: modified retroviral replicating vector with improved stability and gene expression . Mol Ther 2012 ; 20 : 1689 – 98 . doi: 10.1038/mt.2012.83 . Google Scholar Crossref Search ADS PubMed WorldCat 117. Hiraoka K , Inagaki A, Kato Y, Huang TT, Mitchell LA, Kamijima S, et al. Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity . Neuro Oncol 2017 ; 19 : 918 – 29 . doi: 10.1093/neuonc/nox038 . Google Scholar Crossref Search ADS PubMed WorldCat 118. Ostertag D , Amundson KK, Lopez Espinoza F, Martin B, Buckley T, da Silva APG, et al. Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-fluorouracil using a nonlytic retroviral replicating vector . Neuro Oncol 2011 ; 14 : 145 – 59 . doi: 10.1093/neuonc/nor199 . Google Scholar Crossref Search ADS PubMed WorldCat 119. Mitchell LA , Lopez Espinoza F, Mendoza D, Kato Y, Inagaki A, Hiraoka K, et al. Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model . Neuro Oncol 2017 ; 19 : 930 – 9 . doi: 10.1093/neuonc/nox037 . Google Scholar Crossref Search ADS PubMed WorldCat 120. Cloughesy TF , Landolfi J, Hogan DJ, Bloomfield S, Carter B, Chen CC, et al. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma . Sci Transl Med 2016 ; 8 : 341ra75 . doi: 10.1126/scitranslmed.aad9784 . Google Scholar Crossref Search ADS PubMed WorldCat 121. Cloughesy TF , Landolfi J, Vogelbaum MA, Ostertag D, Elder JB, Bloomfield S, et al. Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC . Neuro Oncol 2018 ; 20 : 1383 – 92 . doi: 10.1093/neuonc/noy075 . Google Scholar Crossref Search ADS PubMed WorldCat 122. Hogan DJ , Zhu JJ, Diago OR, Gammon D, Haghighi A, Lu G, et al. Molecular analyses support the safety and activity of retroviral replicating vector Toca 511 in patients . Clin Cancer Res 2018 ; 24 : 4680 – 93 . doi: 10.1158/1078-0432.CCR-18-0619 . Google Scholar Crossref Search ADS PubMed WorldCat 123. Cloughesy T , Petrecca K, Walbert T, Butowski N, Salacz M, Perry J, et al. LTBK-08. TOCA 511 & TOCA fc versus standard of care in patients with recurrent high grade GLIOMA . Neuro Oncol 2019 ; 21 : vi284 . doi: 10.1093/neuonc/noz219.1199 . Google Scholar Crossref Search ADS WorldCat 124. Margolin K , Ernstoff MS, Hamid O, Lawrence D, McDermott D, Puzanov I, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial . Lancet Oncol 2012 ; 13 : 459 – 65 . doi: 10.1016/S1470-2045(12)70090-6 . Google Scholar Crossref Search ADS PubMed WorldCat 125. Di Giacomo AM , Ascierto PA, Pilla L, Santinami M, Ferrucci PF, Giannarelli D, et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial . Lancet Oncol 2012 ; 13 : 879 – 86 . doi: 10.1016/S1470-2045(12)70324-8 . Google Scholar Crossref Search ADS PubMed WorldCat 126. Queirolo P , Spagnolo F, Ascierto PA, Simeone E, Marchetti P, Scoppola A, et al. Efficacy and safety of ipilimumab in patients with advanced melanoma and brain metastases . J Neurooncol 2014 ; 118 : 109 – 16 . doi: 10.1007/s11060-014-1400-y . Google Scholar PubMed OpenURL Placeholder Text WorldCat 127. Heller K , Pavlick A, Hodi F, Thompson J, Margolin K, Lawrence D, et al. Safety and survival analysis of ipilimumab therapy in patients with stable asymptomatic brain metastases . J Clin Oncol 2011 ; 29 : 8581 . doi: 10.1200/jco.2011.29.15_suppl.8581 . Google Scholar Crossref Search ADS WorldCat 128. Goldberg SB , Gettinger SN, Mahajan A, Chiang AC, Herbst RS, Sznol M, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial . Lancet Oncol 2016 ; 17 : 976 – 83 . doi: 10.1016/S1470-2045(16)30053-5 . Google Scholar Crossref Search ADS PubMed WorldCat 129. Long GV , Atkinson V, Lo S, Sandhu S, Guminski AD, Brown MP, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study . Lancet Oncol 2018 ; 19 : 672 – 81 . doi: 10.1016/S1470-2045(18)30139-6 . Google Scholar Crossref Search ADS PubMed WorldCat 130. Priceman SJ , Tilakawardane D, Jeang B, Aguilar B, Murad JP, Park AK, et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2 . Clin Cancer Res 2018 ; 24 : 95 – 105 . doi: 10.1158/1078-0432.CCR-17-2041 . Google Scholar Crossref Search ADS PubMed WorldCat 131. Ahmed N , Brawley VS, Hegde M, Robertson C, Ghazi A, Gerken C, et al. Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma . J Clin Oncol 2015 ; 33 : 1688 – 96 . doi: 10.1200/JCO.2014.58.0225 . Google Scholar Crossref Search ADS PubMed WorldCat 132. Ahmed N , Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial . JAMA Oncol 2017 ; 3 : 1094 – 101 . doi: 10.1001/jamaoncol.2017.0184 . Google Scholar Crossref Search ADS PubMed WorldCat 133. Johnson BE , Mazor T, Hong C, Barnes M, Aihara K, McLean CY, et al. Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma . Science 2014 ; 343 : 189 – 93 . doi: 10.1126/science.1239947 . Google Scholar Crossref Search ADS PubMed WorldCat 134. Razavi SM , Lee KE, Jin BE, Aujla PS, Gholamin S, Li G. Immune evasion strategies of glioblastoma . Front Surg 2016 ; 3 : 11 . doi: 10.3389/fsurg.2016.00011 . Google Scholar Crossref Search ADS PubMed WorldCat 135. Uyttenhove C , Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase . Nat Med 2003 ; 9 : 1269 – 74 . doi: 10.1038/nm934 . Google Scholar Crossref Search ADS PubMed WorldCat 136. Wei J , Barr J, Kong LY, Wang Y, Wu A, Sharma AK, et al. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway . Mol Cancer Ther 2010 ; 9 : 67 – 78 . doi: 10.1158/1535-7163 . Google Scholar Crossref Search ADS PubMed WorldCat 137. Wainwright DA , Balyasnikova IV, Chang AL, Ahmed AU, Moon KS, Auffinger B, et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival . Clin Cancer Res 2012 ; 18 : 6110 – 21 . doi: 10.1158/1078-0432.CCR-12-2130 , PubMed PMID: 22932670; PubMed Central PMCID: PMCPMC3500434 . Google Scholar Crossref Search ADS PubMed WorldCat 138. Galea I , Bechmann I, Perry VH. What is immune privilege (not)? Trends Immunol 2007 ; 28 : 12 – 8 . doi: 10.1016/j.it.2006.11.004 . Google Scholar Crossref Search ADS PubMed WorldCat 139. Dunn GP , Okada H. Principles of immunology and its nuances in the central nervous system . Neuro Oncol 2015 ; 17 : vii3 – 8 . doi: 10.1093/neuonc/nov175 . Google Scholar Crossref Search ADS PubMed WorldCat 140. Sampetrean O , Saga I, Nakanishi M, Sugihara E, Fukaya R, Onishi N, et al. Invasion precedes tumor mass formation in a malignant brain tumor model of genetically modified neural stem cells . Neoplasia 2011 ; 13 : 784 – 91 . doi: 10.1593/neo.11624 . Google Scholar Crossref Search ADS PubMed WorldCat 141. Drumm MR , Dixit KS, Grimm S, Kumthekar P, Lukas RV, Raizer JJ, et al. Extensive brainstem infiltration, not mass effect, is a common feature of end-stage cerebral glioblastomas . Neuro Oncol 2020 ; 22 : 470 – 9 . doi: 10.1093/neuonc/noz216 . Google Scholar Crossref Search ADS PubMed WorldCat 142. Chen DS , Mellman I. Oncology meets immunology: the cancer-immunity cycle . Immunity 2013 ; 39 : 1 – 10 . doi: 10.1016/j.immuni.2013.07.012 . Google Scholar Crossref Search ADS PubMed WorldCat 143. Hatterer E , Davoust N, Didier-Bazes M, Vuaillat C, Malcus C, Belin MF, et al. How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes . Blood 2006 ; 107 : 806 – 12 . doi: 10.1182/blood-2005-01-0154 . Google Scholar Crossref Search ADS PubMed WorldCat 144. Engelhardt B , Carare RO, Bechmann I, Flügel A, Laman JD, Weller RO. Vascular, glial, and lymphatic immune gateways of the central nervous system . Acta Neuropathol 2016 ; 132 : 317 – 38 . doi: 10.1007/s00401-016-1606-5 . Google Scholar Crossref Search ADS PubMed WorldCat 145. Cserr HF , Knopf PM. Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view . Immunol Today 1992 ; 13 : 507 – 12 . doi: 10.1016/0167-5699(92)90027-5 . Google Scholar Crossref Search ADS PubMed WorldCat 146. Owens T , Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation . J Neuropathol Exp Neurol 2008 ; 67 : 1113 – 21 . doi: 10.1097/NEN.0b013e31818f9ca8 . Google Scholar Crossref Search ADS PubMed WorldCat 147. Mastorakos P , McGavern D. The anatomy and immunology of vasculature in the central nervous system . Sci Immunol 2019 ; 4 . doi: 10.1126/sciimmunol.aav0492 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 148. O'Rourke DM , Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma . Sci Transl Med 2017 ; 9 . doi: 10.1126/scitranslmed.aaa0984 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 149. Broz ML , Binnewies M, Boldajipour B, Nelson AE, Pollack JL, Erle DJ, et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity . Cancer Cell 2014 ; 26 : 638 – 52 . doi: 10.1016/j.ccell.2014.09.007 . Google Scholar Crossref Search ADS PubMed WorldCat 150. Korn T , Kallies A. T cell responses in the central nervous system . Nat Rev Immunol 2017 ; 17 : 179 – 94 . doi: 10.1038/nri.2016.144 . Google Scholar Crossref Search ADS PubMed WorldCat 151. Brown NF , Carter TJ, Ottaviani D, Mulholland P. Harnessing the immune system in glioblastoma . Br J Cancer 2018 ; 119 : 1171 – 81 . doi: 10.1038/s41416-018-0258-8 . Google Scholar Crossref Search ADS PubMed WorldCat 152. Ratnam NM , Gilbert MR, Giles AJ. Immunotherapy in CNS cancers: the role of immune cell trafficking . Neuro Oncol 2019 ; 21 : 37 – 46 . doi: 10.1093/neuonc/noy084 . Google Scholar Crossref Search ADS PubMed WorldCat 153. Iliff JJ , Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β . Sci Transl Med 2012 ; 4 : 147ra11 . doi: 10.1126/scitranslmed.3003748 . Google Scholar Crossref Search ADS WorldCat 154. Carare RO , Bernardes-Silva M, Newman TA, Page AM, Nicoll JA, Perry VH, et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology . Neuropathol Appl Neurobiol 2008 ; 34 : 131 – 44 . doi: 10.1111/j.1365-2990.2007.00926.x . Google Scholar Crossref Search ADS PubMed WorldCat 155. Abbott NJ , Pizzo ME, Preston JE, Janigro D, Thorne RG. The role of brain barriers in fluid movement in the CNS: is there a `glymphatic' system? Acta Neuropathol 2018 ; 135 : 387 – 407 . doi: 10.1007/s00401-018-1812-4 . Google Scholar Crossref Search ADS PubMed WorldCat 156. Herz J , Filiano AJ, Smith A, Yogev N, Kipnis J. Myeloid cells in the central nervous system . Immunity 2017 ; 46 : 943 – 56 . doi: 10.1016/j.immuni.2017.06.007 . Google Scholar Crossref Search ADS PubMed WorldCat 157. Sánchez-Paulete AR , Teijeira A, Cueto FJ, Garasa S, Pérez-Gracia JL, Sánchez-Arráez A, et al. Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy . Ann Oncol 2017 ; 28 : xii44 – 55 . doi: 10.1093/annonc/mdx237 . Google Scholar Crossref Search ADS PubMed WorldCat 158. Takenaka MC , Gabriely G, Rothhammer V, Mascanfroni ID, Wheeler MA, Chao CC, et al. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39 . Nat Neurosci 2019 ; 22 : 729 – 40 . doi: 10.1038/s41593-019-0370-y . Google Scholar Crossref Search ADS PubMed WorldCat 159. Komohara Y , Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas . J Pathol 2008 ; 216 : 15 – 24 . doi: 10.1002/path.2370 . Google Scholar Crossref Search ADS PubMed WorldCat 160. Hussain SF , Yang D, Suki D, Aldape K, Grimm E, Heimberger AB. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses . Neuro Oncol 2006 ; 8 : 261 – 79 . doi: 10.1215/15228517-2006-008 . Google Scholar Crossref Search ADS PubMed WorldCat 161. De Smedt T , Van Mechelen M, De Becker G, Urbain J, Leo O, Moser M. Effect of interleukin-10 on dendritic cell maturation and function . Eur J Immunol 1997 ; 27 : 1229 – 35 . doi: 10.1002/eji.1830270526 . Google Scholar Crossref Search ADS PubMed WorldCat 162. Yamaguchi Y , Tsumura H, Miwa M, Inaba K. Contrasting effects of TGF-beta 1 and TNF-alpha on the development of dendritic cells from progenitors in mouse bone marrow . Stem Cells 1997 ; 15 : 144 – 53 . doi: 10.1002/stem.150144 . Google Scholar Crossref Search ADS PubMed WorldCat 163. Berghoff AS , Kiesel B, Widhalm G, Wilhelm D, Rajky O, Kurscheid S, et al. Correlation of immune phenotype with IDH mutation in diffuse glioma . Neuro Oncol 2017 ; 19 : 1460 – 8 . doi: 10.1093/neuonc/nox054 . Google Scholar Crossref Search ADS PubMed WorldCat 164. Layer JP , Kronmüller MT, Quast T, van den Boorn-Konijnenberg D, Effern M, Hinze D, et al. Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression . Onco Targets Ther 2017 ; 6 : e1320626 . doi: 10.1080/2162402X.2017.1320626 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 165. Friebel E , Kapolou K, Unger S, Núñez NG, Utz S, Rushing EJ, et al. Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes . Cell 2020 ; 181 : 1626 – 42.e20 . doi: 10.1016/j.cell.2020.04.055 . Google Scholar Crossref Search ADS PubMed WorldCat 166. Klemm F , Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S, et al. Interrogation of the microenvironmental landscape in brain Tumors reveals disease-specific alterations of immune cells . Cell 2020 ; 181 :1643–60.e17. doi: 10.1016/j.cell.2020.05.007 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 167. Wen PY , Reardon DA, Armstrong TS, Phuphanich S, Aiken RD, Landolfi JC, et al. A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma . Clin Cancer Res 2019 . doi: 10.1158/1078-0432.CCR-19-0261 . Google Scholar OpenURL Placeholder Text WorldCat Crossref 168. Fenstermaker RA , Ciesielski MJ, Qiu J, Yang N, Frank CL, Lee KP, et al. Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma . Cancer Immunol Immunother 2016 ; 65 : 1339 – 52 . doi: 10.1007/s00262-016-1890-x . Google Scholar Crossref Search ADS PubMed WorldCat 169. Liau LM , Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, et al. First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma . J Transl Med 2018 ; 16 : 142 . doi: 10.1186/s12967-018-1507-6 . Google Scholar Crossref Search ADS PubMed WorldCat 170. Wang D , Starr R, Chang WC, Aguilar B, Alizadeh D, Wright SL, et al. Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma . Sci Transl Med 2020 ; 12 :eaaw2672. doi: 10.1126/scitranslmed.aaw2672 . Google Scholar OpenURL Placeholder Text WorldCat Crossref © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - The current state of immunotherapy for primary and secondary brain tumors: similarities and differences
JF - Japanese Journal of Clinical Oncology
DO - 10.1093/jjco/hyaa164
DA - 2020-10-22
UR - https://www.deepdyve.com/lp/oxford-university-press/the-current-state-of-immunotherapy-for-primary-and-secondary-brain-Bi8xC2gafc
SP - 1231
EP - 1245
VL - 50
IS - 11
DP - DeepDyve
ER -