First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell... Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate‑ pulsed dendritic cell vaccine (DCVax ‑ L) to standard therapy for newly diagnosed glioblastoma. Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax‑ L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax‑ L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results: For the intent‑ to‑ treat (ITT ) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross‑ over trial design, nearly 90% of the ITT population received DCVax‑ L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3‑ year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan‑ Meier (KM)‑ derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM‑ derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 *Correspondence: lliau@mednet.ucla.edu; marnix@nwbio.com University of California Los Angeles (UCLA) David Geffen School of Medicine & Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA Northwest Biotherapeutics Inc., Bethesda, MD, USA Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liau et al. J Transl Med (2018) 16:142 Page 2 of 9 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions: Addition of DCVax‑L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https ://clini caltr ials. gov/ct2/show/NCT00 04596 8?term=NCT00 04596 8&rank=1; initially registered 19 September 2002 Keywords: Glioblastoma, Immunotherapy, Dendritic cell, Vaccine to fully elucidate patient survival data in the tail of the Background survival curve. Glioblastoma is the most aggressive primary malig- nant brain tumor in adults [1]. Standard of care (SOC) consists of surgical resection followed by 6  weeks of daily radiotherapy with concurrent temozolomide, then Methods monthly temozolomide [2]. Median overall survival Study patients (mOS) under this SOC is only 15–17  months [2, 3], Patients were eligible for this study if they were and ≤ 5% of patients are alive at 5 years [3]. Loco-regional 18–70  years of age and had newly diagnosed glioblas- therapy with alternating electric fields has recently shown toma, as determined through central pathology review. an increase in median PFS (mPFS) to 6.7  months and Other eligibility criteria included Karnofsky Perfor- mOS to 20.9  months from randomization, respectively mance Score (KPS) of ≥ 70 [20], adequate bone marrow, [4]. However, there has been no material advance in sur- liver, and renal function, life expectancy of ≥ 8  weeks , vival with systemic therapies since the addition of temo- no other prior malignancy within the last 5  years, no zolomide 12  years ago, despite investigations with many active viral infections, and sufficient resected tumor diverse agents [2, 5–10]. material to produce the autologous vaccine. Patients Immunotherapy is an appealing strategy because of the were excluded if they already had apparent early dis- potential ability for immune cells to traffic to and destroy ease progression/recurrence or pseudo-progression at infiltrating tumor cells. Dendritic cells (DCs) are central the baseline visit, similar to the inclusion/exclusion cri- to the immune system as key regulators of immune tol- teria of other recent trials in glioblastoma [4, 21]. erance and immunity [11]. For more than a decade, our group and others have been testing active vaccination Study design and treatments strategies, such as DCs pulsed with tumor lysates or syn- We conducted this study at over 80 sites in 4 countries: thetic peptides to induce antitumor immunity in glioblas- the US, Canada, Germany, and the UK. Patient recruit- toma patients [12, 13]. We have previously demonstrated ment was initiated in 2007, and was paused from 2009 the effectiveness of DC vaccination in pre-clinical models to 2011 for economic reasons. The midpoint of enroll - [14–16], and early stage clinical trials have shown sub- ment was reached in May of 2014, and the final patient stantial promise [17–19]. was enrolled in November of 2015. The protocol was In this report, we describe the blinded interim data of approved by the required independent ethics commit- the overall ITT patient population enrolled in a Phase 3 tees and institutional review boards. Written consent was randomized, double-blinded, placebo-controlled clini- obtained from all patients participating in the trial. cal trial of an autologous tumor lysate-pulsed dendritic All patients underwent surgical resection and 6  weeks cell vaccine (D CVax -L) for newly diagnosed glio- of chemoradiotherapy per SOC, prior to enrollment and blastoma. To date, we have not yet reached sufficient randomization in the study. events (i.e., deaths) in this trial to justify unblinding. Randomization was performed centrally and was strati- Nevertheless, since the vast majority (86.4%) of the ITT fied by clinical site and MGMT (O -methylguanine-DNA population received the experimental DC treatment at methyltransferase) gene promoter methylation status, some point during the trial because of the cross-over which was determined by a central laboratory. Patients study design, analysis of the interim data may provide were randomized 2:1 to SOC plus autologous DC vac- early insight into the impact of DCVax-L on overall cine (DCVax-L; n = 232) or SOC plus placebo (n = 99). survival. A final analysis of the data obtained in this PBMCs were used as placebo control as these cells are trial following unblinding will occur once sufficient visually indistinguishable from DC and are consid- events of disease progression or death have occurred ered immunologically inactive. Patients in both arms Liau et al. J Transl Med (2018) 16:142 Page 3 of 9 continued to receive monthly adjuvant temozolomide Criteria (version 3.0 NCI CTC), until 2 months after the (150–200  mg/m /day × 5  days every 28  days), inter- last study treatment. Patients are followed for OS until spersed with the DC vaccine or placebo treatments death. administered on Days 0, 10 and 20, then Months 2, 4 and 8, and thereafter at 6-month intervals starting at month Statistical analyses 12. Each DCVax-L treatment involved a dose of 2.5 mil- The study’s primary endpoint is  PFS, and the secondary lion autologous tumor lysate-pulsed DCs administered endpoint is OS. PFS has not yet been evaluated for this intradermally in the upper arm, alternating arms between publication and will be the subject of later analyses to injection visits. allow for central, multi-factorial assessment by an expert All patients were allowed to receive DCVax-L following panel, using criteria currently emerging as appropriate tumor progression/recurrence, as well as other approved for immune therapy in this patient population where pro- treatments per local practice. All parties (investigators, gression can be complex to determine and pseudo-pro- patients and sponsor) remained blinded as to which gression is a known confounding phenomenon. Analysis treatment each patient had received prior to crossover. of the blinded interim data on OS of the ITT population All patients who chose this option were given the active (using SAS version 9.4) was performed 34  months after treatment on a re-start schedule with immunizations at the midpoint of patient enrollment, and 16 months after Days 0, 10 and 20, and then months 2, 4 and 8, and every the last patient was enrolled and randomized. 6 months thereafter beginning with month 12, with Day 0 General descriptive statistics include the number of being the day of the first vaccination post progression. To observed values, mean, standard deviation, median, and date, DCVax-L has been shipped for 286 patients (86.4%) range values for continuous measures. For categorical in the trial. variables, the number and percentage of subjects with Both the study treatment (DCVax-L) and placebo a specific level of the variable are reported. For survival (PBMC) were prepared by Cognate BioServices, Inc. for analyses, Kaplan–Meier (KM) curves were generated, all patients in the US and Canada, and by Cognate and yielding estimates of median survival times, along with the Fraunhofer Institute for Cell Therapy together for the two-sided confidence intervals (95% CIs) and esti - patients in Europe, during the chemoradiotherapy period mates of survival at specific time points. before the baseline visit. The production of DCVax- L involved processing the resected tumor tissue into a Results lysate, and then collection, purification, differentiation, Study patients activation and loading of the autologous DCs. In general, From July 2007 to November 2015, 331 patients were approximately 2 g of tumor tissue was needed to produce recruited in the trial, comprising the intent-to-treat the full ten doses for the 36-month treatment and follow- (ITT) population. A flow diagram depicting the flow of up schedule. The vaccine was aliquoted in individual patients through the screening and enrollment process is doses and cryopreserved at < 150 °C [22]. The doses were provided in Fig. 1. The median time from surgery to ran - stored centrally, and shipped individually to the clinical domization was 3.1 months. trial sites. The ITT population (n = 331) (Table  1) is similar to other recent glioblastoma trials [4, 21, 24], with 61% males Assessments (n = 202) and 39% females (n = 129), with 75.2% of the Baseline assessments included physical examination, neu- patients ≥ 50 years of age (range 19–73 years), and median rological examination, vitals, KPS, MRI of brain with and KPS of 90. 63.1% of patients (n = 209) had gross total without contrast, hematology (CBC with differential, plate - resection and 36.9% (n = 122) did not. The MGMT gene lets), and serum chemistries (calcium, magnesium, SGOT, promoter was methylated in 39.6% of patients (n = 131) SGPT, alkaline phosphatase, LDH, total bilirubin, BUN, and unmethylated in 48.9% (n = 162), with information not creatinine, electrolytes, glucose). Blood was collected for available for 11.5% (n = 38; the missing data relates to the serum markers of autoimmune disease (anti-DNA) and early patients enrolled a decade ago). Absolute lymphocyte immune monitoring, at the baseline visit and at treatment count (ALC) was > 800  cells/mm in 48.6% of the patients visits throughout the trial. MRI brain scans were performed (n = 161) and was < 800  cells/mm in 51.4% of patients every 2 months, per SOC, after the baseline MRI until radi- (n = 170), a characteristic that has been associated with ological tumor progression. All MRI scans were evaluated poor prognosis after radiation [23]. Patients with radio- centrally by 2 blinded independent radiologists, with adju- graphic evidence of disease progression at baseline were dication by a third such radiologist if needed. excluded, as they have also been excluded in other recent Adverse events were recorded prospectively according trials for newly diagnosed glioblastoma [4, 21, 24]. to the National Cancer Institute’s Common Terminology Liau et al. J Transl Med (2018) 16:142 Page 4 of 9 Table 1 Baseline demographic and clinical characteristics Variable n = 331 (100%) Age (year) Mean (SD) 55.33 (10.01) Median (range) 56 (19, 73) Sex, n (%) Female 129 (39.0) Male 202 (61.0) Race, n (%) American Indian or Alaska Native 1 (0.3) Asian 2 (0.6) Black or African American 7 (2.1) Hispanic or Latino 16 (4.8) White 294 (88.8) Not a vailable 11 (3.3) KPS at baseline, n (%) < 90 97 (29.3) ≥ 90 234 (70.7) MGMT classification, n (%) Fig. 1 Recruitment, inclusion, and randomization of patients in the Methylated 131 (39.6) study. (1) Patients are screened prior to surgery, so glioblastoma (GBM) determination is made from pathological diagnosis Not methylated 162 (48.9) after surgery. (2) Insufficient tumor lysate generated to meet Not available 38 (11.5) threshold. (3) Progressive disease or pseudo‑progression (which Lymphocyte group, n (%) are indistinguishable at this point) based on central review of MRI High 161 (48.6) imaging at baseline post‑ chemoradiation. (4) Patients who consented Low 170 (51.4) to tumor donation but then declined participation in trial prior to leukapheresis. (5) Includes deviations from standard chemoradiation Surgical status, n (%) protocol, history of prior malignancy, inadequate renal or bone Partial resection 122 (36.9) marrow function, etc. (6) Includes drug product failure or insufficient Complete resection 209 (63.1) drug or placebo manufactured to meet release criteria. (7) Includes Race is in some cases not collected due to institutional policy clinical deterioration, declining Karnofsky performance status, or patient deaths. (8) Includes biopsy only, surgery canceled, or tumor tissue not processed after surgery Long tail among ITT population With immune-based therapies, a key focus is on the tail Since other treatments were allowed following disease of the survival curve [26]. Among the ITT patients with progression, we assessed their usage in this trial. While a surgery date ≥ 30 months prior to the data collection (n on study, three patients (1%) had another resection, 103 = 223), 30% (n = 67) have lived ≥ 30  months, and their patients (31%) received bevacizumab, 53 patients (16%) KM-derived mOS estimate is 46.5  months. Among the received CCNU and 6 patients (1.8%) were treated with ITT patients with a surgery date ≥ 36  months prior to tumor treating fields. In multiple reported studies, nei - the data collection  (n = 182), 24.2% (n =  44)  have lived ther bevacizumab nor CCNU have been shown to extend ≥ 36  months and their KM-derived mOS estimate is survival [9, 25]. 88.2 months. Treatment outcomes MGMT status and extent of resection ITT population In patients with methylated MGMT (n = 131), mOS was At the time of this analysis, 108 the 331 patients (32.6%) 34.7 months from surgery (95% CI 27.0–40.7), with 2 and were still alive. The mOS of the overall ITT population 3-year survival rates of 66.7% and 46.4%, respectively. In (n = 331) was 23.1 months from the time of surgery (95% patients with unmethylated MGMT (n = 162), mOS was CI 21.2–25.4), with 2 and 3-year survival rates of 46.2 19.8 months from surgery (95% CI 17.9–21.7), with 2 and and 25.4%, respectively (see Fig.  2a  and Table  2). Analy- 3-year survival rates of 32.1%, and 11.0%, respectively sis of patient survival relative to year of enrollment did (Fig. 2b and Table 2). not reveal a trend over time, nor meaningful differences For patients with gross total surgical resection between years. (n = 209), mOS was 25.4  months from surgery (95% CI Liau et al. J Transl Med (2018) 16:142 Page 5 of 9 Fig. 2 Overall survival curves for patients in the intent‑to ‑treat population. Overall survival analyses of time from date of surgery until death or last follow‑up according to the Kaplan–Meier method for all patients in the intent ‑to ‑treat (ITT ) population (a), and the ITT population stratified by MGMT gene promoter methylation status (b). Censored patients are annotated by a small vertical line 21.8–28.2), with 2 and 3-year survival rates of 51.2%, and In patients with both MGMT methylation and gross 29.9%, respectively. For patients with only partial surgical total resection (n = 83), the mOS was 36.5  months (95% resection (n = 122), mOS from surgery was 21.1  months CI 31.5–46.5)—1.8  months longer than the mOS of (95% CI 19.1–23.1), with 2 and 3-year survival rates of patients with MGMT methylation and only partial resec- 37.7%, and 18.0%, respectively (Table 2). tion (n = 48). In patients with unmethylated MGMT, Liau et al. J Transl Med (2018) 16:142 Page 6 of 9 Table 2 Study endpoints according to molecular genetic and clinical prognostic subgroups b b b Population n Median OS Survival at 1 year Survival at 2 years Survival at 3 years since surgery (months) Overall 331 23.1 89.3% 46.2% 25.4% (21.2, 25.4) (85.4, 92.2) (40.4, 51.8) (19.9, 31.3) MGMT methylated 131 34.7 94.5% 66.7% 46.4% (27.0, 40.7) (88.8, 97.3) (57.5, 74.4) (35.8, 56.3) MGMT un‑methylated 162 19.8 86.4% 32.1% 11.0% (17.9, 21.7) (80.0, 90.8) (24.5, 9.9) (5.7, 18.2) Gross total resection 209 25.4 91.8% 51.2% 29.9% (21.8, 28.2) (87.1, 94.8) (43.9, 58.1) (22.6, 37.5) Partial resection 122 21.1 85.0% 37.7% 18.0% (19.1, 23.1) (77.2, 90.2) (28.6, 46.7) (10.5, 27.1) KPS at baseline ≥ 90 234 23.7 94.0% 49.2% 26.6% (21.8, 26.7) (90.0, 96.4) (42.3, 55.8) (19.9, 33.8) KPS at baseline < 90 97 19.8 77.8% 38.8% 22.1% (16.6, 23.9) (68.0, 84.9) (28.5, 49.0) (13.4, 32.2) ALC > 800 161 23.6 89.9% 49.5% 28.7% (21.7, 28.2) (84.0, 93.7) (41.1, 57.4) (20.6, 37.3) ALC ≤ 800 170 21.6 88.7% 43.3% 22.2% (19.9, 25.2) (82.8, 92.6) (35.4, 50.9) (15.0, 30.3) Age < 50 years 82 26.2 92.5% 51.7% 28.0% (21.1, 31.5) (84.2, 96.6) (39.9, 62.3) (16.4, 40.8) Age ≥ 50 years 249 22.4 88.2% 44.4% 24.6% (20.4, 24.1) (83.5, 91.7) (37.7, 50.8) (18.5, 31.2) Median overall survival (OS) in months of intent-to-treat (ITT ) population, followed by 95% confidence interval in parentheses Annual rates of percentage surviving in ITT population, followed by 95% confidence interval in parentheses there was no statistically significant survival advan - or possibly related to the DCVax-L treatment. These tage with gross total resection compared to only partial included cerebral edema in 3 patients (0.9%), seizures in resection. 2 patients (0.6%), nausea in 1 patient (0.3%) and lymph gland infection in 1 patient (0.3%). The rate of total adverse events with SOC plus DCVax- Unknown factors: sub‑group with extended survival L was comparable to SOC alone (Table  3). Non-serious Approximately 30% of the ITT population (n = 100) adverse events that were considered possibly related to showed particularly extended survival, with a KM the treatment included injection site reactions, fatigue, derived mOS estimate of 40.5  months. This is not fully low-grade fever and night chills. explained by known prognostic factors, as only some of these patients had positive prognostic factors: only 29% Discussion were younger than 50 years of age, 65.9% had methylated Although enrollment was completed in 2015, this trial, MGMT, 71% had a complete resection, and only 8% of including both treatments and follow-up, is still ongoing these patients had all three positive prognostic factors. and will remain blinded until sufficient events of disease These patients will be the subject of extensive further progression and/or death have occurred to more fully analyses and research. elucidate the tail of the survival curve. To date, due to the crossover design, nearly 90% of the ITT population Safety and toxicity received DCVax-L at some point in the trial, due to the Safety and toxicity data were assessed on a blinded basis crossover design. for all 331 ITT patients. Following SOC chemoradio- DCVax-L is administered by intra-dermal injection in therapy, and before any DCVax-L treatment, lymphope- the arm, six times in year one and twice per year there- nia was the most common adverse event, occurring in after. It thereby imposes only a minimal burden on the approximately 170 patients (51%) [23]. patient. The DCVax-L treatment was well tolerated, with only In the overall ITT population in this trial, the mOS of 7 ITT patients (2.1%) experiencing serious (NCI CTC 23.1  months from surgery compares favorably with the Grades 3–4) adverse events that were deemed related mOS of 15–17  months from surgery typically achieved Liau et al. J Transl Med (2018) 16:142 Page 7 of 9 Table 3 Grades 3–4 treatment-emergent adverse events in trial designs a decade ago when this trial began. It will (TEAE) be collected and analyzed later, but is unlikely to explain a the overall survival results, as the mutation associated System organ class Number (%) of patients with TEAE with prolonged survival occurs in less than 10% of newly (n = 331) diagnosed glioblastoma patients [27]. Beneficial effects of immune therapies are often Patients reporting at least one serious TEAE 137 (41.1%) (whether or not related to DC vaccine treat‑ observed at later time points, in the tail of the survival ment) curve [26]. Although this Phase 3 trial requires fur- Nervous system disorders 93 (28.1%) ther maturation, a picture is beginning to emerge from Infections 23 (6.9%) the blinded interim data which is consistent with an General disorders and injection site reactions 22 (6.6%) extended survival tail. For example, among the patients Respiratory, thoracic and mediastinal disorders 17 (5.1%) (n = 182) who were ≥ 36  months past their surgery date Psychiatric disorders 16 (4.8%) as of the date of this analysis, 24.2% (n = 44) were alive Gastrointestinal disorders 16 (4.8%) for ≥ 36  months and have a KM estimated median sur- Injury, poisoning, and procedural complications 12 (3.6%) vival time of 88.2  months. u Th s, it appears that patients Vascular disorders 6 (1.8%) who survive past certain threshold time points may con- Musculoskeletal and connective tissue disor‑ 5 (1.5%) tinue onwards to unusually long survival times, similar ders to the findings in our prior Phase I/II studies of this DC- Neoplasms benign, malignant and unspecified 5 (1.5%) based vaccine [17–19]. Further maturation of the trial Hematological disorders 5 (1.5%) data is needed to more fully reveal the extent of the long Metabolism and nutrition disorders 3 (0.9%) tail of the survival curve. Hepatobiliary disorders 2 (0.6%) DCVax-L has shown a benign safety profile in this Renal and urinary disorders 2 (0.6%) Phase 3 study, as it has consistently done in prior early Cardiac disorders 1 (0.3%) stage trials [17, 19], and in a large group of patients Ear and labyrinth disorders 1 (0.3%) treated on a compassionate use basis [28]. The fact that Immune system disorders 1 (0.3%) only 7 of the 331 ITT patients (2.1%) experienced any Reproductive system and breast disorders 1 (0.3%) grade 3 or 4 adverse events that were at least possibly Coded per MedDRA 16.0. Patients may have had more than one adverse event, related to the treatment makes this DC vaccine an espe- so subcategories do not total cially well tolerated treatment. Includes surgical wound infections, meningitis, urinary tract infections, and With such a safety profile, this DC vaccine may be others administered in a wide range of clinical settings, and Includes drug hypersensitivity can potentially be combined with a wide range of other with SOC in past studies and clinical practice, as well as treatment agents, including immune checkpoint inhibi- with the survival data with SOC treatment in the control tors and targeted therapies, without resulting in undue arms of other trials in similar patient populations. For toxicities for patients such as have been seen with some example, Weller et al. reported mOS of 17.4 months from other treatment combinations [29, 30]. Further studies to randomization in the ITT population [21], and Stupp explore such combinations are warranted. et al. reported mOS of 16.0 months from randomization in the ITT population [24]. Conclusions In patients with a methylated MGMT gene promoter, The addition of DCVax-L autologous dendritic cell vac - the mOS of 34.7  months from surgery also compares cine to SOC is feasible and safe. Collectively, the blinded favorably with SOC in past studies as well as with the interim survival data suggest that the patients in this mOS reported for the control arm SOC treatments in Phase 3 trial are living longer than expected. These find - other recent glioblastoma trials in similar patient popu- ings warrant further follow up and analyses. lations. For example, Stupp et al. reported for their con- Authors’ contributions trol group an  mOS of 21.2  months from randomization LL and MB conceived of and designed the study. LL, KA, DDT, JLC, TET, CSC, in a similar patient population [24]. The increase in JAH, MS, ST, SDD, FMI, EJD, YAM, KAW, CPP, RA, RC, SAG, DAB, PD, JG, HE, SAT, survival in MGMT-methylated patients in the DCVax- KOL, TM, TW, SRA, AJB, SB, MGE, AK, JP, LJK, WGL, RCT, DEA, KLF, FJG, SL, JL, AES, GS, DK, H‑ JM, JW, RPD, CD, ABE, DM, SK, DP, MW, DSB, PZN, ML, S‑AM, TJP, VT, L trial raises the possibility of a cooperative effect from RMG, JLV, MP, KP, MS, LPT, and PM contributed to collection of the data. EB the combination of temozolomide chemotherapy and the served as the consulting statistician. All authors were involved in critical review DCVax-L active immune therapy [17]. of the data, or drafting, reviewing or revising the manuscript or approving the final version. LL enrolled the greatest number of patients in the USA and The mutation status of the IDH1 gene has not yet been KA enrolled the greatest number of patients in the EU. All authors read and investigated for this trial, as this factor was not included approved the final manuscript. Liau et al. J Transl Med (2018) 16:142 Page 8 of 9 Author details Funding University of California Los Angeles (UCLA) David Geffen School of Medicine Northwest Biotherapeutics, Inc. was the trial sponsor and had a role in the & Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. King’s Col‑ design and conduct of the study, along with academic advisers; collection, lege London School of Medical Education, London, UK. University of Florida, management, analysis, and interpretation of the data; preparation, review, and 4 5 Gainesville, FL, USA. Washington University, St. Louis, MO, USA. Abbott approval of the manuscript; and decision to submit the manuscript for publi‑ Northwestern Hospital, Minneapolis, MN, USA. Swedish Medical Center, cation. Data collected by the CRO from the investigators and their site person‑ Swedish Neuroscience Institute, Seattle, WA, USA. University of Michigan nel were analyzed and interpreted on a blinded basis by senior academic Medical School, Ann Arbor, MI, USA. University of Kansas Cancer Center, Kan‑ authors, independent statisticians, and representatives of the sponsor. sas City, KS, USA. Sutter Institute for Medical Research, Sacramento, CA, USA. 10 11 Columbia University Medical Center, New York, NY, USA. Indiana University 12 Publisher’s Note Simon Cancer Center, Indianapolis, IN, USA. Overlook Medical Center, Sum‑ 13 Springer Nature remains neutral with regard to jurisdictional claims in pub‑ mit, NJ, USA. University of Rochester Medical Center, Rochester, NY, USA. 14 15 lished maps and institutional affiliations. Rush University Medical Center, Rochester, USA. Rutgers Cancer Institute, New Brunswick, NJ, USA. University of Cincinnati Medical Center, Cincinnati, 17 18 Received: 27 April 2018 Accepted: 7 May 2018 OH, USA. Hackensack University Medical Center, Hackensack, NJ, USA. 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Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier Klinikum Chemnitz GGMBH, Chemnitz, Germany. Saint Luke’s Cancer Insti‑ AF, Cher LM, Mason W, Weller M, Hong S, Musib L, et al. Phase III study tute, Kansas City, MO, USA. Kaiser Permanente Northern California, Redwood of enzastaurin compared with lomustine in the treatment of recurrent City, CA, USA. Kaiser Permanente Southern California, Los Angeles, CA, USA. 52 53 intracranial glioblastoma. J Clin Oncol. 2010;28(7):1168–74. University of Kentucky College of Medicine, Lexington, KY, USA. Colorado 6. Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Neurological Institute, Englewood, CO, USA. Montreal Neurological Institute Mason W, Mikkelsen T, Phuphanich S, Ashby LS, et al. Phase III randomized and Hospital, McGill University, Montreal, Canada. Northwell Hofstra School trial comparing the efficacy of cediranib as monotherapy, and in combi‑ of Medicine, Lake Success, NY, USA. Department of Neurology, Alvord Brain nation with lomustine, versus lomustine alone in patients with recurrent Tumor Center, University of Washington, Seattle, WA, USA. University College glioblastoma. J Clin Oncol. 2013;31(26):3212–8. Hospitals, London, UK. Northwest Biotherapeutics Inc., Bethesda, MD, USA. 7. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, NYU Winthrop Hospital, Mineola, NY, USA. Lhermitte B, Pietsch T, Grujicic D, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma Acknowledgements with methylated MGMT promoter (CENTRIC EORTC 26071‑22072 study): Supported by Northwest Biotherapeutics, Inc. and the UCLA SPORE in Brain a multicentre, randomised, open‑label, phase 3 trial. Lancet Oncol. Cancer (P50‑ CA211015). We thank the patients who have participated in this 2014;15(10):1100–8. clinical trial and their families. 8. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogel‑ baum MA, Colman H, Chakravarti A, Pugh S, Won M, et al. A randomized Competing interests trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. Dr. Bosch and Dr. Maida report being an employee of, holding stock or stock 2014;370(8):699–708. options in, and receiving reimbursement for travel expenses from Northwest 9. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Car‑ Biotherapeutics, Inc. pentier AF, Hoang‑ Xuan K, Kavan P, Cernea D, et al. Bevacizumab plus radiotherapy‑temozolomide for newly diagnosed glioblastoma. N Engl J Availability of data and materials Med. 2014;370(8):709–22. The datasets generated and/or analyzed during the current study are not 10. Westphal M, Heese O, Steinbach JP, Schnell O, Schackert G, Mehdorn M, publicly available to protect future regulatory filings but access to the data Schulz D, Simon M, Schlegel U, Senft C, et al. A randomised, open label can be available through an independent statistician on a case by case basis, phase III trial with nimotuzumab, an anti‑ epidermal growth factor recep‑ as necessary and under confidentiality. tor monoclonal antibody in the treatment of newly diagnosed adult glioblastoma. Eur J Cancer. 2015;51(4):522–32. Consent for publication 11. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Not applicable. Rev Cancer. 2012;12(4):265–77. 12. Hickey MJ, Malone CC, Erickson KL, Jadus MR, Prins RM, Liau LM, Kruse CA. Ethics approval and consent to participate Cellular and vaccine therapeutic approaches for gliomas. J Transl Med. The study was approved by Ethics Committees/Institutional Review boards at 2010;8:100. all participating hospitals. Written consent was obtained from all patients prior to participating in the study. Liau et al. J Transl Med (2018) 16:142 Page 9 of 9 13. Prins RM, Liau LM. Cellular immunity and immunotherapy of brain 22. 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Bevacizumab alone and tion in glioblastoma patients induces systemic and intracranial T‑ cell in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. responses modulated by the local central nervous system tumor micro‑ 2009;27(28):4733–40. environment. Clin Cancer Res. 2005;11(15):5515–25. 26. Harris SJ, Brown J, Lopez J, Yap TA. Immuno‑ oncology combinations: rais‑ 18. Prins RM, Cloughesy TF, Liau LM. Cytomegalovirus immunity after ing the tail of the survival curve. Cancer Biol Med. 2016;13(2):171–93. vaccination with autologous glioblastoma lysate. N Engl J Med. 27. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, 2008;359(5):539–41. Carter H, Siu IM, Gallia GL, et al. An integrated genomic analysis of human 19. Prins RM, Soto H, Konkankit V, Odesa SK, Eskin A, Yong WH, Nelson SF, Liau glioblastoma multiforme. Science. 2008;321(5897):1807–12. LM. Gene expression profile correlates with T ‑ cell infiltration and relative 28. Bosch ML, Prins RM. Prolonged survival for patients with recurrent survival in glioblastoma patients vaccinated with dendritic cell immuno‑ glioblastoma multiforme who are treated with tumour lysate‑pulsed therapy. Clin Cancer Res. 2011;17(6):1603–15. autologous dendritic cells. Eur J Cancer. 2015;51(Supplement 1):S6–7. 20. Curran WJ Jr, Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, 29. Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J, Suijker‑ Chang CH, Rotman M, Asbell SO, Krisch RE, et al. Recursive partitioning buijk KPM, Azevedo S, Li H, Reshef D, et al. Neurologic serious adverse analysis of prognostic factors in three Radiation Therapy Oncology Group events associated with nivolumab plus ipilimumab or nivolumab alone in malignant glioma trials. J Natl Cancer Inst. 1993;85(9):704–10. advanced melanoma, including a case series of encephalitis. Oncologist. 21. Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, Ashby L, Mech‑ 2017;22(6):709–18. tler L, Goldlust SA, Iwamoto F, et al. Rindopepimut with temozolomide for 30. Maxwell R, Jackson CM, Lim M. Clinical trials investigating immune check‑ patients with newly diagnosed, EGFRvIII‑ expressing glioblastoma (ACT point blockade in glioblastoma. Curr Treat Options Oncol. 2017;18(8):51. IV ): a randomised, double‑blind, international phase 3 trial. Lancet Oncol. 2017;18:1378–85. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. 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Biomedicine; Biomedicine, general; Medicine/Public Health, general
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Abstract

Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate‑ pulsed dendritic cell vaccine (DCVax ‑ L) to standard therapy for newly diagnosed glioblastoma. Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax‑ L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax‑ L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results: For the intent‑ to‑ treat (ITT ) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross‑ over trial design, nearly 90% of the ITT population received DCVax‑ L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3‑ year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan‑ Meier (KM)‑ derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM‑ derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 *Correspondence: lliau@mednet.ucla.edu; marnix@nwbio.com University of California Los Angeles (UCLA) David Geffen School of Medicine & Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA Northwest Biotherapeutics Inc., Bethesda, MD, USA Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liau et al. J Transl Med (2018) 16:142 Page 2 of 9 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions: Addition of DCVax‑L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https ://clini caltr ials. gov/ct2/show/NCT00 04596 8?term=NCT00 04596 8&rank=1; initially registered 19 September 2002 Keywords: Glioblastoma, Immunotherapy, Dendritic cell, Vaccine to fully elucidate patient survival data in the tail of the Background survival curve. Glioblastoma is the most aggressive primary malig- nant brain tumor in adults [1]. Standard of care (SOC) consists of surgical resection followed by 6  weeks of daily radiotherapy with concurrent temozolomide, then Methods monthly temozolomide [2]. Median overall survival Study patients (mOS) under this SOC is only 15–17  months [2, 3], Patients were eligible for this study if they were and ≤ 5% of patients are alive at 5 years [3]. Loco-regional 18–70  years of age and had newly diagnosed glioblas- therapy with alternating electric fields has recently shown toma, as determined through central pathology review. an increase in median PFS (mPFS) to 6.7  months and Other eligibility criteria included Karnofsky Perfor- mOS to 20.9  months from randomization, respectively mance Score (KPS) of ≥ 70 [20], adequate bone marrow, [4]. However, there has been no material advance in sur- liver, and renal function, life expectancy of ≥ 8  weeks , vival with systemic therapies since the addition of temo- no other prior malignancy within the last 5  years, no zolomide 12  years ago, despite investigations with many active viral infections, and sufficient resected tumor diverse agents [2, 5–10]. material to produce the autologous vaccine. Patients Immunotherapy is an appealing strategy because of the were excluded if they already had apparent early dis- potential ability for immune cells to traffic to and destroy ease progression/recurrence or pseudo-progression at infiltrating tumor cells. Dendritic cells (DCs) are central the baseline visit, similar to the inclusion/exclusion cri- to the immune system as key regulators of immune tol- teria of other recent trials in glioblastoma [4, 21]. erance and immunity [11]. For more than a decade, our group and others have been testing active vaccination Study design and treatments strategies, such as DCs pulsed with tumor lysates or syn- We conducted this study at over 80 sites in 4 countries: thetic peptides to induce antitumor immunity in glioblas- the US, Canada, Germany, and the UK. Patient recruit- toma patients [12, 13]. We have previously demonstrated ment was initiated in 2007, and was paused from 2009 the effectiveness of DC vaccination in pre-clinical models to 2011 for economic reasons. The midpoint of enroll - [14–16], and early stage clinical trials have shown sub- ment was reached in May of 2014, and the final patient stantial promise [17–19]. was enrolled in November of 2015. The protocol was In this report, we describe the blinded interim data of approved by the required independent ethics commit- the overall ITT patient population enrolled in a Phase 3 tees and institutional review boards. Written consent was randomized, double-blinded, placebo-controlled clini- obtained from all patients participating in the trial. cal trial of an autologous tumor lysate-pulsed dendritic All patients underwent surgical resection and 6  weeks cell vaccine (D CVax -L) for newly diagnosed glio- of chemoradiotherapy per SOC, prior to enrollment and blastoma. To date, we have not yet reached sufficient randomization in the study. events (i.e., deaths) in this trial to justify unblinding. Randomization was performed centrally and was strati- Nevertheless, since the vast majority (86.4%) of the ITT fied by clinical site and MGMT (O -methylguanine-DNA population received the experimental DC treatment at methyltransferase) gene promoter methylation status, some point during the trial because of the cross-over which was determined by a central laboratory. Patients study design, analysis of the interim data may provide were randomized 2:1 to SOC plus autologous DC vac- early insight into the impact of DCVax-L on overall cine (DCVax-L; n = 232) or SOC plus placebo (n = 99). survival. A final analysis of the data obtained in this PBMCs were used as placebo control as these cells are trial following unblinding will occur once sufficient visually indistinguishable from DC and are consid- events of disease progression or death have occurred ered immunologically inactive. Patients in both arms Liau et al. J Transl Med (2018) 16:142 Page 3 of 9 continued to receive monthly adjuvant temozolomide Criteria (version 3.0 NCI CTC), until 2 months after the (150–200  mg/m /day × 5  days every 28  days), inter- last study treatment. Patients are followed for OS until spersed with the DC vaccine or placebo treatments death. administered on Days 0, 10 and 20, then Months 2, 4 and 8, and thereafter at 6-month intervals starting at month Statistical analyses 12. Each DCVax-L treatment involved a dose of 2.5 mil- The study’s primary endpoint is  PFS, and the secondary lion autologous tumor lysate-pulsed DCs administered endpoint is OS. PFS has not yet been evaluated for this intradermally in the upper arm, alternating arms between publication and will be the subject of later analyses to injection visits. allow for central, multi-factorial assessment by an expert All patients were allowed to receive DCVax-L following panel, using criteria currently emerging as appropriate tumor progression/recurrence, as well as other approved for immune therapy in this patient population where pro- treatments per local practice. All parties (investigators, gression can be complex to determine and pseudo-pro- patients and sponsor) remained blinded as to which gression is a known confounding phenomenon. Analysis treatment each patient had received prior to crossover. of the blinded interim data on OS of the ITT population All patients who chose this option were given the active (using SAS version 9.4) was performed 34  months after treatment on a re-start schedule with immunizations at the midpoint of patient enrollment, and 16 months after Days 0, 10 and 20, and then months 2, 4 and 8, and every the last patient was enrolled and randomized. 6 months thereafter beginning with month 12, with Day 0 General descriptive statistics include the number of being the day of the first vaccination post progression. To observed values, mean, standard deviation, median, and date, DCVax-L has been shipped for 286 patients (86.4%) range values for continuous measures. For categorical in the trial. variables, the number and percentage of subjects with Both the study treatment (DCVax-L) and placebo a specific level of the variable are reported. For survival (PBMC) were prepared by Cognate BioServices, Inc. for analyses, Kaplan–Meier (KM) curves were generated, all patients in the US and Canada, and by Cognate and yielding estimates of median survival times, along with the Fraunhofer Institute for Cell Therapy together for the two-sided confidence intervals (95% CIs) and esti - patients in Europe, during the chemoradiotherapy period mates of survival at specific time points. before the baseline visit. The production of DCVax- L involved processing the resected tumor tissue into a Results lysate, and then collection, purification, differentiation, Study patients activation and loading of the autologous DCs. In general, From July 2007 to November 2015, 331 patients were approximately 2 g of tumor tissue was needed to produce recruited in the trial, comprising the intent-to-treat the full ten doses for the 36-month treatment and follow- (ITT) population. A flow diagram depicting the flow of up schedule. The vaccine was aliquoted in individual patients through the screening and enrollment process is doses and cryopreserved at < 150 °C [22]. The doses were provided in Fig. 1. The median time from surgery to ran - stored centrally, and shipped individually to the clinical domization was 3.1 months. trial sites. The ITT population (n = 331) (Table  1) is similar to other recent glioblastoma trials [4, 21, 24], with 61% males Assessments (n = 202) and 39% females (n = 129), with 75.2% of the Baseline assessments included physical examination, neu- patients ≥ 50 years of age (range 19–73 years), and median rological examination, vitals, KPS, MRI of brain with and KPS of 90. 63.1% of patients (n = 209) had gross total without contrast, hematology (CBC with differential, plate - resection and 36.9% (n = 122) did not. The MGMT gene lets), and serum chemistries (calcium, magnesium, SGOT, promoter was methylated in 39.6% of patients (n = 131) SGPT, alkaline phosphatase, LDH, total bilirubin, BUN, and unmethylated in 48.9% (n = 162), with information not creatinine, electrolytes, glucose). Blood was collected for available for 11.5% (n = 38; the missing data relates to the serum markers of autoimmune disease (anti-DNA) and early patients enrolled a decade ago). Absolute lymphocyte immune monitoring, at the baseline visit and at treatment count (ALC) was > 800  cells/mm in 48.6% of the patients visits throughout the trial. MRI brain scans were performed (n = 161) and was < 800  cells/mm in 51.4% of patients every 2 months, per SOC, after the baseline MRI until radi- (n = 170), a characteristic that has been associated with ological tumor progression. All MRI scans were evaluated poor prognosis after radiation [23]. Patients with radio- centrally by 2 blinded independent radiologists, with adju- graphic evidence of disease progression at baseline were dication by a third such radiologist if needed. excluded, as they have also been excluded in other recent Adverse events were recorded prospectively according trials for newly diagnosed glioblastoma [4, 21, 24]. to the National Cancer Institute’s Common Terminology Liau et al. J Transl Med (2018) 16:142 Page 4 of 9 Table 1 Baseline demographic and clinical characteristics Variable n = 331 (100%) Age (year) Mean (SD) 55.33 (10.01) Median (range) 56 (19, 73) Sex, n (%) Female 129 (39.0) Male 202 (61.0) Race, n (%) American Indian or Alaska Native 1 (0.3) Asian 2 (0.6) Black or African American 7 (2.1) Hispanic or Latino 16 (4.8) White 294 (88.8) Not a vailable 11 (3.3) KPS at baseline, n (%) < 90 97 (29.3) ≥ 90 234 (70.7) MGMT classification, n (%) Fig. 1 Recruitment, inclusion, and randomization of patients in the Methylated 131 (39.6) study. (1) Patients are screened prior to surgery, so glioblastoma (GBM) determination is made from pathological diagnosis Not methylated 162 (48.9) after surgery. (2) Insufficient tumor lysate generated to meet Not available 38 (11.5) threshold. (3) Progressive disease or pseudo‑progression (which Lymphocyte group, n (%) are indistinguishable at this point) based on central review of MRI High 161 (48.6) imaging at baseline post‑ chemoradiation. (4) Patients who consented Low 170 (51.4) to tumor donation but then declined participation in trial prior to leukapheresis. (5) Includes deviations from standard chemoradiation Surgical status, n (%) protocol, history of prior malignancy, inadequate renal or bone Partial resection 122 (36.9) marrow function, etc. (6) Includes drug product failure or insufficient Complete resection 209 (63.1) drug or placebo manufactured to meet release criteria. (7) Includes Race is in some cases not collected due to institutional policy clinical deterioration, declining Karnofsky performance status, or patient deaths. (8) Includes biopsy only, surgery canceled, or tumor tissue not processed after surgery Long tail among ITT population With immune-based therapies, a key focus is on the tail Since other treatments were allowed following disease of the survival curve [26]. Among the ITT patients with progression, we assessed their usage in this trial. While a surgery date ≥ 30 months prior to the data collection (n on study, three patients (1%) had another resection, 103 = 223), 30% (n = 67) have lived ≥ 30  months, and their patients (31%) received bevacizumab, 53 patients (16%) KM-derived mOS estimate is 46.5  months. Among the received CCNU and 6 patients (1.8%) were treated with ITT patients with a surgery date ≥ 36  months prior to tumor treating fields. In multiple reported studies, nei - the data collection  (n = 182), 24.2% (n =  44)  have lived ther bevacizumab nor CCNU have been shown to extend ≥ 36  months and their KM-derived mOS estimate is survival [9, 25]. 88.2 months. Treatment outcomes MGMT status and extent of resection ITT population In patients with methylated MGMT (n = 131), mOS was At the time of this analysis, 108 the 331 patients (32.6%) 34.7 months from surgery (95% CI 27.0–40.7), with 2 and were still alive. The mOS of the overall ITT population 3-year survival rates of 66.7% and 46.4%, respectively. In (n = 331) was 23.1 months from the time of surgery (95% patients with unmethylated MGMT (n = 162), mOS was CI 21.2–25.4), with 2 and 3-year survival rates of 46.2 19.8 months from surgery (95% CI 17.9–21.7), with 2 and and 25.4%, respectively (see Fig.  2a  and Table  2). Analy- 3-year survival rates of 32.1%, and 11.0%, respectively sis of patient survival relative to year of enrollment did (Fig. 2b and Table 2). not reveal a trend over time, nor meaningful differences For patients with gross total surgical resection between years. (n = 209), mOS was 25.4  months from surgery (95% CI Liau et al. J Transl Med (2018) 16:142 Page 5 of 9 Fig. 2 Overall survival curves for patients in the intent‑to ‑treat population. Overall survival analyses of time from date of surgery until death or last follow‑up according to the Kaplan–Meier method for all patients in the intent ‑to ‑treat (ITT ) population (a), and the ITT population stratified by MGMT gene promoter methylation status (b). Censored patients are annotated by a small vertical line 21.8–28.2), with 2 and 3-year survival rates of 51.2%, and In patients with both MGMT methylation and gross 29.9%, respectively. For patients with only partial surgical total resection (n = 83), the mOS was 36.5  months (95% resection (n = 122), mOS from surgery was 21.1  months CI 31.5–46.5)—1.8  months longer than the mOS of (95% CI 19.1–23.1), with 2 and 3-year survival rates of patients with MGMT methylation and only partial resec- 37.7%, and 18.0%, respectively (Table 2). tion (n = 48). In patients with unmethylated MGMT, Liau et al. J Transl Med (2018) 16:142 Page 6 of 9 Table 2 Study endpoints according to molecular genetic and clinical prognostic subgroups b b b Population n Median OS Survival at 1 year Survival at 2 years Survival at 3 years since surgery (months) Overall 331 23.1 89.3% 46.2% 25.4% (21.2, 25.4) (85.4, 92.2) (40.4, 51.8) (19.9, 31.3) MGMT methylated 131 34.7 94.5% 66.7% 46.4% (27.0, 40.7) (88.8, 97.3) (57.5, 74.4) (35.8, 56.3) MGMT un‑methylated 162 19.8 86.4% 32.1% 11.0% (17.9, 21.7) (80.0, 90.8) (24.5, 9.9) (5.7, 18.2) Gross total resection 209 25.4 91.8% 51.2% 29.9% (21.8, 28.2) (87.1, 94.8) (43.9, 58.1) (22.6, 37.5) Partial resection 122 21.1 85.0% 37.7% 18.0% (19.1, 23.1) (77.2, 90.2) (28.6, 46.7) (10.5, 27.1) KPS at baseline ≥ 90 234 23.7 94.0% 49.2% 26.6% (21.8, 26.7) (90.0, 96.4) (42.3, 55.8) (19.9, 33.8) KPS at baseline < 90 97 19.8 77.8% 38.8% 22.1% (16.6, 23.9) (68.0, 84.9) (28.5, 49.0) (13.4, 32.2) ALC > 800 161 23.6 89.9% 49.5% 28.7% (21.7, 28.2) (84.0, 93.7) (41.1, 57.4) (20.6, 37.3) ALC ≤ 800 170 21.6 88.7% 43.3% 22.2% (19.9, 25.2) (82.8, 92.6) (35.4, 50.9) (15.0, 30.3) Age < 50 years 82 26.2 92.5% 51.7% 28.0% (21.1, 31.5) (84.2, 96.6) (39.9, 62.3) (16.4, 40.8) Age ≥ 50 years 249 22.4 88.2% 44.4% 24.6% (20.4, 24.1) (83.5, 91.7) (37.7, 50.8) (18.5, 31.2) Median overall survival (OS) in months of intent-to-treat (ITT ) population, followed by 95% confidence interval in parentheses Annual rates of percentage surviving in ITT population, followed by 95% confidence interval in parentheses there was no statistically significant survival advan - or possibly related to the DCVax-L treatment. These tage with gross total resection compared to only partial included cerebral edema in 3 patients (0.9%), seizures in resection. 2 patients (0.6%), nausea in 1 patient (0.3%) and lymph gland infection in 1 patient (0.3%). The rate of total adverse events with SOC plus DCVax- Unknown factors: sub‑group with extended survival L was comparable to SOC alone (Table  3). Non-serious Approximately 30% of the ITT population (n = 100) adverse events that were considered possibly related to showed particularly extended survival, with a KM the treatment included injection site reactions, fatigue, derived mOS estimate of 40.5  months. This is not fully low-grade fever and night chills. explained by known prognostic factors, as only some of these patients had positive prognostic factors: only 29% Discussion were younger than 50 years of age, 65.9% had methylated Although enrollment was completed in 2015, this trial, MGMT, 71% had a complete resection, and only 8% of including both treatments and follow-up, is still ongoing these patients had all three positive prognostic factors. and will remain blinded until sufficient events of disease These patients will be the subject of extensive further progression and/or death have occurred to more fully analyses and research. elucidate the tail of the survival curve. To date, due to the crossover design, nearly 90% of the ITT population Safety and toxicity received DCVax-L at some point in the trial, due to the Safety and toxicity data were assessed on a blinded basis crossover design. for all 331 ITT patients. Following SOC chemoradio- DCVax-L is administered by intra-dermal injection in therapy, and before any DCVax-L treatment, lymphope- the arm, six times in year one and twice per year there- nia was the most common adverse event, occurring in after. It thereby imposes only a minimal burden on the approximately 170 patients (51%) [23]. patient. The DCVax-L treatment was well tolerated, with only In the overall ITT population in this trial, the mOS of 7 ITT patients (2.1%) experiencing serious (NCI CTC 23.1  months from surgery compares favorably with the Grades 3–4) adverse events that were deemed related mOS of 15–17  months from surgery typically achieved Liau et al. J Transl Med (2018) 16:142 Page 7 of 9 Table 3 Grades 3–4 treatment-emergent adverse events in trial designs a decade ago when this trial began. It will (TEAE) be collected and analyzed later, but is unlikely to explain a the overall survival results, as the mutation associated System organ class Number (%) of patients with TEAE with prolonged survival occurs in less than 10% of newly (n = 331) diagnosed glioblastoma patients [27]. Beneficial effects of immune therapies are often Patients reporting at least one serious TEAE 137 (41.1%) (whether or not related to DC vaccine treat‑ observed at later time points, in the tail of the survival ment) curve [26]. Although this Phase 3 trial requires fur- Nervous system disorders 93 (28.1%) ther maturation, a picture is beginning to emerge from Infections 23 (6.9%) the blinded interim data which is consistent with an General disorders and injection site reactions 22 (6.6%) extended survival tail. For example, among the patients Respiratory, thoracic and mediastinal disorders 17 (5.1%) (n = 182) who were ≥ 36  months past their surgery date Psychiatric disorders 16 (4.8%) as of the date of this analysis, 24.2% (n = 44) were alive Gastrointestinal disorders 16 (4.8%) for ≥ 36  months and have a KM estimated median sur- Injury, poisoning, and procedural complications 12 (3.6%) vival time of 88.2  months. u Th s, it appears that patients Vascular disorders 6 (1.8%) who survive past certain threshold time points may con- Musculoskeletal and connective tissue disor‑ 5 (1.5%) tinue onwards to unusually long survival times, similar ders to the findings in our prior Phase I/II studies of this DC- Neoplasms benign, malignant and unspecified 5 (1.5%) based vaccine [17–19]. Further maturation of the trial Hematological disorders 5 (1.5%) data is needed to more fully reveal the extent of the long Metabolism and nutrition disorders 3 (0.9%) tail of the survival curve. Hepatobiliary disorders 2 (0.6%) DCVax-L has shown a benign safety profile in this Renal and urinary disorders 2 (0.6%) Phase 3 study, as it has consistently done in prior early Cardiac disorders 1 (0.3%) stage trials [17, 19], and in a large group of patients Ear and labyrinth disorders 1 (0.3%) treated on a compassionate use basis [28]. The fact that Immune system disorders 1 (0.3%) only 7 of the 331 ITT patients (2.1%) experienced any Reproductive system and breast disorders 1 (0.3%) grade 3 or 4 adverse events that were at least possibly Coded per MedDRA 16.0. Patients may have had more than one adverse event, related to the treatment makes this DC vaccine an espe- so subcategories do not total cially well tolerated treatment. Includes surgical wound infections, meningitis, urinary tract infections, and With such a safety profile, this DC vaccine may be others administered in a wide range of clinical settings, and Includes drug hypersensitivity can potentially be combined with a wide range of other with SOC in past studies and clinical practice, as well as treatment agents, including immune checkpoint inhibi- with the survival data with SOC treatment in the control tors and targeted therapies, without resulting in undue arms of other trials in similar patient populations. For toxicities for patients such as have been seen with some example, Weller et al. reported mOS of 17.4 months from other treatment combinations [29, 30]. Further studies to randomization in the ITT population [21], and Stupp explore such combinations are warranted. et al. reported mOS of 16.0 months from randomization in the ITT population [24]. Conclusions In patients with a methylated MGMT gene promoter, The addition of DCVax-L autologous dendritic cell vac - the mOS of 34.7  months from surgery also compares cine to SOC is feasible and safe. Collectively, the blinded favorably with SOC in past studies as well as with the interim survival data suggest that the patients in this mOS reported for the control arm SOC treatments in Phase 3 trial are living longer than expected. These find - other recent glioblastoma trials in similar patient popu- ings warrant further follow up and analyses. lations. For example, Stupp et al. reported for their con- Authors’ contributions trol group an  mOS of 21.2  months from randomization LL and MB conceived of and designed the study. LL, KA, DDT, JLC, TET, CSC, in a similar patient population [24]. The increase in JAH, MS, ST, SDD, FMI, EJD, YAM, KAW, CPP, RA, RC, SAG, DAB, PD, JG, HE, SAT, survival in MGMT-methylated patients in the DCVax- KOL, TM, TW, SRA, AJB, SB, MGE, AK, JP, LJK, WGL, RCT, DEA, KLF, FJG, SL, JL, AES, GS, DK, H‑ JM, JW, RPD, CD, ABE, DM, SK, DP, MW, DSB, PZN, ML, S‑AM, TJP, VT, L trial raises the possibility of a cooperative effect from RMG, JLV, MP, KP, MS, LPT, and PM contributed to collection of the data. EB the combination of temozolomide chemotherapy and the served as the consulting statistician. All authors were involved in critical review DCVax-L active immune therapy [17]. of the data, or drafting, reviewing or revising the manuscript or approving the final version. LL enrolled the greatest number of patients in the USA and The mutation status of the IDH1 gene has not yet been KA enrolled the greatest number of patients in the EU. All authors read and investigated for this trial, as this factor was not included approved the final manuscript. Liau et al. J Transl Med (2018) 16:142 Page 8 of 9 Author details Funding University of California Los Angeles (UCLA) David Geffen School of Medicine Northwest Biotherapeutics, Inc. was the trial sponsor and had a role in the & Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA. King’s Col‑ design and conduct of the study, along with academic advisers; collection, lege London School of Medical Education, London, UK. University of Florida, management, analysis, and interpretation of the data; preparation, review, and 4 5 Gainesville, FL, USA. Washington University, St. Louis, MO, USA. Abbott approval of the manuscript; and decision to submit the manuscript for publi‑ Northwestern Hospital, Minneapolis, MN, USA. Swedish Medical Center, cation. Data collected by the CRO from the investigators and their site person‑ Swedish Neuroscience Institute, Seattle, WA, USA. University of Michigan nel were analyzed and interpreted on a blinded basis by senior academic Medical School, Ann Arbor, MI, USA. University of Kansas Cancer Center, Kan‑ authors, independent statisticians, and representatives of the sponsor. sas City, KS, USA. Sutter Institute for Medical Research, Sacramento, CA, USA. 10 11 Columbia University Medical Center, New York, NY, USA. Indiana University 12 Publisher’s Note Simon Cancer Center, Indianapolis, IN, USA. Overlook Medical Center, Sum‑ 13 Springer Nature remains neutral with regard to jurisdictional claims in pub‑ mit, NJ, USA. University of Rochester Medical Center, Rochester, NY, USA. 14 15 lished maps and institutional affiliations. Rush University Medical Center, Rochester, USA. Rutgers Cancer Institute, New Brunswick, NJ, USA. University of Cincinnati Medical Center, Cincinnati, 17 18 Received: 27 April 2018 Accepted: 7 May 2018 OH, USA. Hackensack University Medical Center, Hackensack, NJ, USA. 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Journal of Translational MedicineSpringer Journals

Published: May 29, 2018

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