Pharm Res (2018) 35:152 https://doi.org/10.1007/s11095-018-2436-z EXPERT REVIEW Chimeric Antigen Receptor T-Cells (CAR T-Cells) for Cancer Immunotherapy – Moving Target for Industry? 1 1 1 Paula Salmikangas & Niamh Kinsella & Paul Chamberlain Received: 3 April 2018 /Accepted: 23 May 2018 # The Author(s) 2018 ABSTRACT The first CD19 CAR T-cell products, ABBREVIATIONS Kymriah and Yescarta, are entering the US market and also Ab Antibody being evaluated for marketing authorization in the EU. This AE Adverse event breakthrough has expanded the interest and also investments ALL Acute lymphoblastic leukemia towards novel chimeric antigen receptor (CAR) designs, both AML Acute myeloid leukemia for hematological malignancies and solid tumors. At the same ATMP Advanced therapy medicinal product time, there is active development in moving from autologous BPDCN Blastic plasmacytoid dendritic cell neoplasm products to allogeneic, off-the-shelf -products. New CAR Chimeric antigen receptor manufacturing technologies are also emerging for production CD Cluster of differentiation of these complex genetically-modified cells and even Crispr Clustered regularly interspaced short decentralized manufacturing in hospitals is under consider- palindromic repeats ation. However, the high potency of CAR T-cells is associated CRS Cytokine release syndrome with toxicity and not all patients respond to the treatment. In DLBCL Diffuse large B-cell lymphoma addition, the number of patient and product variables DSMB Data Safety Monitoring Board impacting the clinical outcome is high. The race towards nov- EGFR Epidermal growth factor receptor el CAR T treatment options for cancer patients has begun, EU European Union but without careful design of the constructs and overall under- FDA Food and Drug Administration standing of the factors that impact the ultimate outcome in GE Gene editing each case, the road towards commercial success may be long GMP Good manufacturing practise and winding. This review discusses the product- and patient- GvHD Graft vs. Host Disease related variables that may pose challenges for the industry and HLA Human leucocyte antigen developers both from the scientific and regulatory perspective. IO Insertional oncogenesis ko Knock out MA Marketing authorisation . . KEY WORDS antigen receptor CAR T genetic MM Multiple myeloma . . modification immunotherapy T-cells NK cell Natural killer cell PBMC Peripheral blood mononuclear cells QP Qualified person R/R Relapsed/refractory scFv Single chain variable fragment Guest Editors: Karin Hoogendoorn and Christopher A. Bravery SOP Standard operating procedure TAA Tumor associated antigen * Paula Salmikangas T-cell T lymphocyte firstname.lastname@example.org TRUCK T cells Redirected for Universal Cytokine-mediated Killing NDA Group,Stockholm,Sweden US United States 152 Page 2 of 8 Salmikangas, Kinsella and Chamberlain (2018) 35:152 INTRODUCTION to the second generation CARs additional co-stimulatory do- main was included. Addition of a single CD28 or 4-1BB Adoptive cancer immunotherapies are developed using differ- costimulatory domain led to improved activation and prolifera- ent cell types and underlying mechanisms; however, common tion of the modified T-cells . More recently it has been found to all of these products is the goal to induce patient’s own that the signals transmitted by the co-stimulatory domains seem immune response against the tumor cells via specific tumor to differ and impact the ultimate T-cell composition and persis- cell recognition and induction of cytotoxicity. This involves tence of the CAR-expressing cells, as well as the tumor responses specific tumor-associated antigens (TAAs), recognized by ge- . Clinical results are also suggesting that these highly activat- netically modified T-cell/NK-cell receptors or chimeric anti- ed T-cells could cause overly high selective pressure in the patient gen receptors (CARs). The first CAR T-cell products, leading to tumor antigen escape and relapse . The capability Yescarta from Kite Pharma/Gilead and Kymriah from of the tumor cells to edit themselves is a challenge and the answer Novartis, were approved by the United States Food and to this problem has been searched from dual CAR Ts, for ex- Drug Administration (US FDA) in 2017, with prominent effi- ample against CD19 and CD20 for B-cell malignancies . cacy results [1, 2]. Both products are intended for treatment of Third generation CAR Ts involve two co-stimulatory domains B-cell malignancies (lymphoma and leukemia) and utilize the (e.g. both CD28 and 4-1BB), whereas the fourth generation con- CD19 antigen as the TAA. CD19 is an ideal target for T-cell structs called TRUCKs (T cells Redirected for Universal mediated killing due to its´ specificity; the expression is restrict- Cytokine-mediated Killing) are armored second generation ed to B-cells and B-cell precursors and it is not found on CARs with additional genetic modifications to enhance anti- hematopoietic stem cells . This minimizes off-target toxicity tumor activity, e.g. expression of cytokines . In addition, and enhances anti-tumor efficacy. Both Yescarta and the first CAR Ts with ablation/safety systems are in early clinical Kymriah are currently under assessment for marketing autho- trials, enabling removal of the cells in case severe or life threat- rization in the European Union (EU) [4, 5], yet for Yescarta ening adverse events jeopardize patients´ survival post adminis- the path has not been straight forward as major objections tration of the cells [7, 19]. were raised during the assessment and the original accelerated Initial CAR T developments have been based on assessment timetable was reverted to the normal review period patients’own (autologous) cells, which are collected while the in December 2017 . In advanced development phase is also patient is receiving standard cancer treatments, and then ge- the CD19 CAR T product JCAR017 from Celgene (originally netically modified via ex-vivo transduction using a product- developed by Juno), for which first clinical results from the specific vector. After transduction a carefully controlled TRANSCEND trial were presented in 2017 . While all manufacturing process is executed to expand the cells, which these three products share the same target and also the same are then administered back to the patient. Yescarta is indicat- binding domain in the CAR construct, there are differences in ed for the treatment of adult patients with relapsed or refrac- the design of the signaling domains of the construct and in tory diffuse large B-cell lymphoma (R/R DLBCL) after two or many aspects of the manufacturing process, including the cell more lines of systemic therapy, whereas Kymriah is indicated population used as starting material for transduction (see for the treatment of patients up to 25 years of age with B-cell Table I.) [8–10]. Other tumor antigens are also utilized in precursor acute lymphoblastic leukemia (ALL) that is refrac- the CARs designed for hematological malignancies, for exam- tory or in second or later relapse [1, 2]. This has posed clear ple CD20 and CD22 for B-cell malignancies, BMCA for mul- challenges, as the health condition and proliferation capacity tiple myeloma and CD123 for myeloid malignancies . of the cells to be transduced may vary significantly between More recently, novel tumor associated antigens (neoantigens) patients, even leading to suboptimal cell numbers for some have come into the center of active research, especially for solid patients. This has moved the interest towards allogeneic (do- tumors  and also the clinical translation of novel products is nated by other individuals), off-the-shelf products, derived strong, which can be seen e.g. from all the clinical trials (> 250) from cells obtained from healthy volunteers and multiple al- with different CAR T-cells registered into ClinicalTrials.gov. logeneic CAR Ts are currently in early clinical studies, includ- The main issue for the neoantigens is specificity, as wide ing projects comparing clinical response in autologous vs. al- expression of the antigen will usually lead also to on-target/off- logeneic setting using the same CAR . tumor toxicity . The CAR T approach for solid tumors also The field of adaptive immunotherapies is fast evolving and faces other challenges, for example the inhibiting tumor novel technologies e.g. for genetic engineering are utilized. Gene environment, poor access to theentiretumor tissuefor CAR editing (GE) is quickly moving the focus away from retro/ T-cells, etc. [12, 13]. In addition, the design of the signaling lentiviral vectors for genetic manipulation of cells, yet the poten- part of the CARs has evolved during the years. The first tial for off-target gene editing and corresponding safety aspects of generation constructs had only one signaling domain, the GE are not fully solved. The products are also becoming more cluster of differentiation 3 zeta (CD3ζ), to induce T-cell activa- and more complex, having more known and unknown risks that tion . This approach, however, led to modest activation and require careful controls and patient follow-up. Novel CAR T-cell Products for Cancer Immunotherapy (2018) 35:152 Page 3 of 8 152 Table I Differences in design, materials and clinical use of first approved autologous CAR T-cell products compared to other CAR T-cells (Autologous and Allogeneic) currently in clinical trials. a b c d Yescarta Kymriah JCAR017 UCART-19 bb21217 (BCMA) Kite/Gilead Novars Celgene Cellecs/Servier BlueBird/Celgene an-CD19 / an-CD19/ an-CD19/ an-CD19/ an-BMCA scFv FMC63 FMC63 FMC63 FMC63 Hinge IgG1 CD8A IgG4 CD8A nk Transmembrane Cosmulatory domain CD28 4-1BB 4-1BB 4-1BB 4-1BB Signalling CD3 CD3 CD3 CD3 CD3 domain + + Cell populaon PBMC PBMC CD4 + CD8 PBMC PBMC None None EGFR RQR8 None Ablaon/safety cetuximab rituximab module None None None TCR /CD52 ko None Other modiﬁcaon Vector Retrovirus Lenvirus Lenvirus GE/Talen Lenvirus CD3/IL-2 CD3/CD28 nk nk nk T-cell acvaon Donor Autologous Autologous Autologous Allogeneic Autologous 6 6 7 6 * Dose 2 × 10 –0.2 x 10 -5 x 10 or 6 x 10 50 – 800 x 8 8 8 + 6 + 2 x 10 /kg 2.5 x 10 /kg 1 x 10 cells CAR cells 10 CAR T cells + + + + CD3 /CAR CD3 /CAR (total) total total ALL DLBCL ALL ALL MM Indicaon MA/US MA/US Post PhI PhI PhI Phase Yescarta, US FDA assessment report  Kymriah, US FDA assessment report  JCAR017 clinical trial [10, 41] Poirot L. et al.  and ASH abstract 887 (2017)  bb21217 clinical trial , BlueBirdBio/Celgene press release  and Garrett et al.  *CALM dose escalation trial, first dose results presented nk = not known Kymriah, Yescarta JCA017 and bb21217 have received the EU PRIME status  152 Page 4 of 8 Salmikangas, Kinsella and Chamberlain (2018) 35:152 FROM AUTOLOGOUS TO ALLOGENEIC profile, thus necessitating proper standardization of the dona- T-CELLS tion and collection of the cells [25, 26]. For allogeneic products, there will be limitations on how far material from one donation As can be expected, expansion and manufacturing of autolo- canbeexpandedand therewillbeneed formultipledonations gous modified T-cells from lymphocytes of heavily treated from one donor or different donors for large scale production. patients is not always easy and successful due to low lympho- For different donors the individual variability on the cellular cyte counts and poor health condition of the cells. The prob- level is usually high, but also cells collected from same donor at lem is highlighted by the results of the Kymriah pivotal trial, different times demonstrate some level of variability. How com- where 9% of the enrolled subjects could not receive the prod- parability between products from different donations/donors uct due to manufacturing failure . Thus, off-the-shelf allo- will be demonstrated remains an open question. geneic CAR T-cells, manufactured from lymphocytes of healthy donors, seem attractive in many ways, yet there are still many issues that hamper their wider use in clinical trials. BALANCE BETWEEN EFFICACY AND SAFETY Allogeneic cells may suffer from the human leucocyte an- tigen (HLA) mismatch between donor and recipient, which in All patients treated with CAR T-cells experience some level of worst case can lead to severe, even life threatening Graft vs. cytokine-release syndrome (CRS), as it is part of the efficacy of Host Disease (GvHD) . Rejection could also remove the the product . CRS is caused by the high activation of T- CAR-expressing cells and lead to treatment failure. To over- cells and destruction of numerous tumor cells at the same time come this problem, HLA knock-out allogeneic CAR T-cells (tumor lysis syndrome), both releasing large amounts of cyto- have been designed, e.g. the anti-CD19 UCART19 from kines . An especially important role is played by IL-6, Cellectis/Servier, where a knock-out design of the αβ T-cell which seems to be secreted by monocyte-lineage cells due to receptors is expected to prevent alloreactivity [22,Table I]. the high CAR T-cell activation . Some treated patients According to first results of the UCART19 CALM trial, in- have experienced a severe form of CRS, sometimes associated volving R/R B-ALL patients, four out of six patients with the with neurotoxicity and even patient deaths have been report- starting dose relapsed 4–6 months post administration and ed in many trials, both with autologous and allogeneic CAR one patient was reported to have probable skin GvHD, sug- T-cells [24, 30]. Severe infections seem also to be frequently gesting presence of partially functional HLA recognition . reported adverse events (AE) for these products and recently The dose for allogeneic CAR T-cells is not as easy to define found to be associated with the grade of CRS . Treatment as for autologous ones, for which already a lot of information is of the severe CRS and neurotoxicity has been focused on available from multiple clinical studies. In addition, the cellular blocking the IL-6 with anti-IL-6 antibody tocilizumab, which growth kinetics of healthy cells is different from cells of diseased does not impact the functionality of the CAR T-cells . patients and very high expansion rate of healthy cells may pose However, for optimal control of each patient it would be im- a safety risk, which needs to be considered in dose selection. For perative to find predictive biomarkers reflecting the patient UCART19, 4 different dose levels are intended, starting with of characteristics that correlate with efficacy and safety out- 6×10 total CAR+ cells, whereas for autologous CAR Ts comes, and also to identify markers for quality controls that 6 8 doses in range of 10 –10 CAR+ T-cells/kg are used. In an- serve the same purpose at the product level. It is already other allogeneic CAR T trial sponsored by Cellectis known that severe CRS is associated with high expansion rate (UCART123), intended to treat patients with acute myeloid of the cells requiring careful consideration of the dose and leukemia (AML) and blastic plasmacytoid dendritic cell neo- follow-up of the growth kinetics of the transduced cells  plasm (BPDCN), the first dosed patient died due to lethal cy- and that cytokines used in growth media for stimulation of the tokine storm and life-threatening capillary leak syndrome . cells before transduction have impact on the efficacy outcome The trial was put on hold by FDA and a recommendation from . Therefore, monitoring of the potency of the transduced the Data Safety Monitoring Board (DSMB) was given to lower CAR T- cells prior to administration, for example by mea- the original dose of 625,000 CAR T + −cells/kg to 62,500 surement of antigen-driven in vitro cell proliferation, as well as CAR-T + −cells/kg, and to reduce the conditioning cyclophos- persistence of transduced cells in vivo, are important for miti- phamide dose. This case illustrates the difficulty of estimating gating these risks. an acceptable starting dose when using CAR T-cells that can As emphasized earlier, a key risk factor for CAR T-cells is undergo relatively strong antigen-driven proliferation, allied to the specificity of the target antigen, as expression on healthy potential for on-target/off-tumor toxicity for an antigen cells can lead to on-target/off-tumor toxicity and significant (CD123) that is expressed on normal tissues. damage to patients´ tissues and organs . CD19 is For autologous cells it is well known that the starting mate- expressed also on healthy B-cells, which can lead to persistent rial has wide inherent variability and that the apheresis proce- B-cell aplasia and hypogammaglobulinemia in CD19 CAR T –treated patients. This, however, can be managed through dure may impact the actual cell composition and product Novel CAR T-cell Products for Cancer Immunotherapy (2018) 35:152 Page 5 of 8 152 replacement therapy and as CD19 is not found on hemato- Very little discussion can be found on the binding domains poietic stem cells, the hematopoietic system is not impacted. of the CAR constructs, yet they comprise an important part of For solid tumors the available antigen targets may not be these molecules. Most CD19 CARs utilize the same murine adequately tissue specific and approaches to increase specific- single chain variable fragment (scFv, FMC63), yet for other B- ity may be required, for example by targeting multiple anti- cell targets and for solid tumors humanized or fully human gens as already explored for B-cell malignancies . Antigen antibody sequences and other binding elements like repeat escape of CD19+ and CD22+ tumors has been documented proteins are utilized . In addition, a human counterpart resulting in relapses during the clinical trials [36, 37]. The for FMC63 has been developed and tested in non-clinical underlying mechanisms have been studied, yet the results models . Human anti-mouse antibodies are known to de- are heterogeneous and demonstrate involvement of alterna- velop against the FMC63 binding domain, yet these have tive splicing (CD19), direct genetic modifications, as well as been considered to have no clinical relevance. However, a correlation with pre-existing mutations [36, 37]. severe case of anaphylaxis has been reported resulting from Although multi-antigen targeting may represent a suitable repeated dosing of a CAR T product with murine mesothelin strategy to improve on-tumor specificity and to minimize risk Ab sequence highlighting the need to also consider the origin of antigen escape, further comparative data is needed to assess of the binding domain especially for repeated dosing . the relationship between clinical response profiles of treated Unclear at the moment is whether repeat use of the same virus CD19- patients and their transduced T-cells. Different factors vectors bears a risk of immune responses against the viral may interact to influence overall clinical benefit and risk, in- capsids in the treated patients, as inevitably some free virus cluding: primary sequence and affinity of the antibody do- is transmitted to the patients with the CAR T-cells. This, mains used for target antigen binding, nature of the co- together with possibility of viral recombination, is the reason stimulatory domains, relative level of cell stimulation and ac- why free virus particles in the final product are expected to be tivation, tumor burden and the dosing strategy, including pre- analyzed and controlled. Concerns are expressed also about conditioning chemotherapy. very high affinity of the antibody fragments, as it may lead to The actual cell composition, in terms of the different T-cell responses against cells that have low levels of target expression subsets, that is administered and expanding in the patient also  and it may also reduce the actual anti-tumor activity . requires additional understanding. In particular, of interest On the other hand, the affinity of the scFvs may be reduced has been the ratio of CD4+ and CD8+ cells for optimal effi- over time in vivo and careful selection of the binding domain is cacy  and persistence of the CAR T+ subsets [39, 40]; critical. Studies of same binding domains with varying affini- however, there is not yet enough data available to make firm ties evaluated side-by-side could be valuable before selection conclusions about the optimal T-cell composition for efficacy of the final construct for clinical studies, especially in case of and safety. Comparison of published results from clinical trials target antigens that are expressed also on non-malignant cells. is hampered by the wide differences in CAR design and actual For autologous products, the best time for cell-based im- manufacturing processes. For JCAR017, a specified ratio of munotherapies needs to be further investigated. It is well CD4+ and CD8+ cells are given to the patients, whereas known that tumor burden is related to the severity of the Kymriah and Yescarta are dosed based on CD3+/CAR T+ CRS , but also the immunological condition of heavily numbers (see Table I)[1, 2, 41] . Some data suggest improved treated patients may be poor and production of sufficient persistence of CAR T-cells with the 4-1BB co-stimulatory do- numbers of good quality CAR T-cells may be difficult. New main, which seems to support maturation of the CD8+ cells trials are designed to study CAR T-cells together with other towards central memory phenotype [39, 42]. According to immuno-oncology products, like anti-PD1 antagonists , most published trials, persistence of the CAR T-cells is re- which are expected to provide also synergic effects for the quired to prevent relapse after the treatment, although the CAR T therapy by modifying the tumor inhibitory exact timeframe required is not clear. However, for a CD19 environment. CAR T product with a CD28 co-stimulatory domain it has been reported that persistence of the CAR T cells does not correlate with long term survival . It has been also pro- posed that CD4+ and CD8+ cells might even require differ- NEXT GENERATION ent co-stimulatory domains for their optimal functionality and interplay in eradicating the tumor cells . In addition to the While the first CAR T-cell products are now entering com- T-cell subsets and the signaling domains of the CAR con- mercial markets, a successful treatment outcome cannot be struct, donor-related factors like age, health status and con- assured for every patient, and severe adverse events can be comitant medication may also impact the final product and expected to occur; CRS may require complex risk manage- need to be taken into account before manufacturing and dose ment algorithms that are not available in all treatment centers. selection. It should be also recognized how fast the science is evolving in 152 Page 6 of 8 Salmikangas, Kinsella and Chamberlain (2018) 35:152 this field, putting the first approved products under heavy manufacturing facilities may pose challenges to the manufac- pressure as the next generation products will soon follow. turers. This has increased the interest towards decentralized The safety issues have raised the interest towards safety manufacturing near the patients and e.g. Miltenyi Biotec has elements (safety switches/suicide genes) that could be intro- been preparing for this opportunity through the novel devices duced into the CARs. For JCAR017, a safety switch com- and by gaining expertise on lentivirus production . However, posed of a truncated form of epidermal growth factor receptor this scenario leaves the question, who is responsible for the prod- (EGFR) was introduced into the CAR construct, thus enabling uct given to the patient? According to the new guideline on good the removal of the transduced cells in emergency situations manufacturing practice (GMP) established for Advanced with anti-EGFR antibody Cetuximab  and the RQR8 Therapy Medicinal Products (ATMPs), the products from domain recognized by rituximab is utilized in the allogeneic decentralized manufacturing, if fulfilling the definition of an product UCART19 . In addition, constructs that would ATMP, are medicinal products for which the legal requirements allow switching the CAR expression on and off are in non- apply . Thus, production of an ATMP in a hospital would clinical development, providing more opportunities to control require same control over the production and over the product, possible toxicities . as is defined for industrial manufacturing. The new GMP guide- Traditionally the vectors used for CARs have been retro- or line for ATMPs specifies that Class D background can be accept- lentiviruses, however, current practice is tending toward ed for fully closed systems, instead of the standard requirement of lentiviral vectors due to their better safety profile. However, Class A in Class B background expected for aseptic production of both types of viral vector have potential to integrate into the medicinal products. Here, it must be noted, that Class D back- host genome, thereby raising the concern of insertional onco- ground also requires specific production premises with full envi- genesis (IO) . The problems with integration have been ronmental monitoring (particles and microbes). The production mainly identified when hematopoietic stem cells have been process has to be validated at each site and the product has to be transduced and no IO cases have been reported for genetically released by a qualified person (QP) against pre-specified and modified T-cells yet. However, when more complex products approved specifications. However, the GMP guideline foresees are designed with multiple CAR targets and knock outs of a possibility to establish a Bcentral site^ with a QP for oversight of original genes of the cells, the risks are cumulative and can be all decentralized sites. This requires written contracts, shared assessed only when results of long-term safety monitoring be- standard operating procedures (SOPs) and understanding of come available. For this reason, monitoring treated subjects for the responsibilities of the QP and production personnel. secondary malignancies, and collecting biopsy specimens to ex- Considering the complexity of the CAR T-cell products, it re- clude a causal relationship with insertional mutagenesis, may mains to be seen, whether decentralized production and central represent an expected risk management activity. Finally, the release of autologous cells would be a viable option or whether trend to use gene editing for CAR T-cell production is raising the allogeneic, off-the-shelf products will conquer the markets. concerns, as for the technology all issues relating to off-target editing are not yet solved . It is noteworthy that TALEN technology has already been utilized for UCART platform by CONCLUSIONS Cellectis/Servier  and Crispr/Cas9 is in preclinical studies for CAR T production . Thebenefitsand risksofthe 3rd The CAR T-cell products have been found to be promising and 4th generation CAR T-cells, compared to the 2nd gener- novel therapies for unmet medical need in the oncology sector ation products, remain to be explored. However, when the and the first products are approved for commercial use. intracellular parts are further engineered, the binding domains Furthermore, hundreds of clinical trials with different CAR should not be forgotten and a holistic approach for novel CAR T-cells are ongoing and the engineering work of next genera- T designs would be valuable, taking into consideration all com- tion constructs is active. Yet the efficacy results of these prod- ponents that may impact the final outcome in humans. ucts have been profound, all patients do not benefit from the treatment and the number of variables that may impact the clinical outcome of each patient treated with a CAR T prod- DECENTRALIZED MANUFACTURING uct is exceptionally high, both in the autologous and alloge- neic approach. In order to mitigate the toxicity and increase Manufacturing of virally transduced cells has raised the need for number of complete responders, holistic design of novel CAR new manufacturing technologies and devices, especially for au- constructs, as well knowledge of all factors impacting the clin- tologous products with small amounts of starting materials. ical outcome is needed. In order to gain better understanding Closed systems that allow aseptic sampling have reached the of this powerful treatment modality, more data both from markets providing solutions that can also be applied for individ- patients and product lots need to be collected, so that suitable ual CAR T manufacturing. Due to the fragility of the transduced biomarkers and product quality controls correlating with safe- cells and short shelf lives, long transportation from the ty and efficacy can be identified. This link between quality and Novel CAR T-cell Products for Cancer Immunotherapy (2018) 35:152 Page 7 of 8 152 7. 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Pharmaceutical Research – Springer Journals
Published: May 31, 2018
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