Expanding Accessibility to CD19-CAR T Cells: Commercializing a “Boutique” Therapy
Authors: Premal Lulla, Carlos A. Ramos
Journal: Molecular Therapy (2017)

T cells genetically modified to target CD19 through a chimeric antigen receptor (CAR) have led to unprecedented clinical responses in patients with refractory CD19-expressing tumors.1Kochenderfer J.N. Dudley M.E. Kassim S.H. Somerville R.P.T. Carpenter R.O. Stetler-Stevenson M. Yang J.C. Phan G.Q. Hughes M.S. Sherry R.M. et al.Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.J. Clin. Oncol. 2015; 33: 540-549Crossref PubMed Scopus (1194) Google Scholar, 2Maude S.L. Frey N. Shaw P.A. Aplenc R. Barrett D.M. Bunin N.J. Chew A. Gonzalez V.E. Zheng Z. Lacey S.F. et al.Chimeric antigen receptor T cells for sustained remissions in leukemia.N. Engl. J. Med. 2014; 371: 1507-1517Crossref PubMed Scopus (3543) Google Scholar, 3Brentjens R.J. Davila M.L. Riviere I. Park J. Wang X. Cowell L.G. Bartido S. Stefanski J. Taylor C. Olszewska M. et al.CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia.Sci. Transl. Med. 2013; 5: 177ra38Crossref PubMed Scopus (1498) Google Scholar Thus far, patient access to CD19 CAR T cell therapy has been limited to a handful of centers through early phase investigator-initiated trials. The paper by Locke et al.4Locke F.L. Neelapu S.S. Bartlett N. Siddiqi T. Chavez J.C. Hosing C.M. Ghobadi A. Budde L.E. Bot A. Rossi J.M. et al.Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma.Mol Ther. 2016; 25 (this issue): 285-295Abstract Full Text Full Text PDF Scopus (404) Google Scholar in this issue of Molecular Therapy is, to our knowledge, the first to report results from a second wave of studies with the common goal of expanding patient access to CAR T cells, thereby moving this treatment toward commercialization. In this industry-sponsored study, Locke et al.4Locke F.L. Neelapu S.S. Bartlett N. Siddiqi T. Chavez J.C. Hosing C.M. Ghobadi A. Budde L.E. Bot A. Rossi J.M. et al.Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma.Mol Ther. 2016; 25 (this issue): 285-295Abstract Full Text Full Text PDF Scopus (404) Google Scholar report phase I data supporting the feasibility of infusing a centrally manufactured autologous CD19 CAR T cell product to patients with refractory diffuse large B cell lymphoma (DLBCL) treated at multiple centers. The study achieves its primary end point of demonstrating safety, thus justifying progression to a larger phase II cohort involving many more centers. Chemotherapy refractory DLBCL is considered incurable and universally fatal in most settings, except for those few patients who are able to successfully undergo an allogeneic stem cell transplant.5Crump M. Neelapu S.S. Farooq U. Neste E.V.D. Kuruvilla J. Ahmed M.A. et al.Outcomes in refractory aggressive diffuse large b-cell lymphoma (DLBCL): Results from the international SCHOLAR-1 study.J. Clin. Oncol. 2016; 34 (abstr 7516)Crossref PubMed Scopus (86) Google Scholar Two decades ago, the introduction of rituximab, a CD20 antibody, induced impressive response rates of 30% to 37% in this challenging patient population.6Coiffier B. Haioun C. Ketterer N. Engert A. Tilly H. Ma D. Johnson P. Lister A. Feuring-Buske M. Radford J.A. et al.Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study.Blood. 1998; 92: 1927-1932PubMed Google Scholar Through subsequent confirmatory trials, the inclusion of rituximab became a paradigm-shifting approach to the management of lymphomas from standard chemotherapy to chemo-immunotherapy. In the present era, we may be witnessing an analogous story unfold with CD19 CAR T cell therapy, which, in early phase trials, has demonstrated remarkable durable complete response (CR) rates (up to 50%) in chemotherapy and rituximab refractory lymphomas.1Kochenderfer J.N. Dudley M.E. Kassim S.H. Somerville R.P.T. Carpenter R.O. Stetler-Stevenson M. Yang J.C. Phan G.Q. Hughes M.S. Sherry R.M. et al.Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.J. Clin. Oncol. 2015; 33: 540-549Crossref PubMed Scopus (1194) Google Scholar, 7Xu Y. Zhang M. Ramos C.A. Durett A. Liu E. Dakhova O. Liu H. Creighton C.J. Gee A.P. Heslop H.E. et al.Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15.Blood. 2014; 123: 3750-3759Crossref PubMed Scopus (422) Google Scholar Whether this is indeed the case will depend on confirming the effectiveness of CD19 CAR T cells in larger multicenter trials. Several features of CD19 CAR T cells contrast sharply with rituximab and other conventional therapeutics, posing logistical challenges to these trials. First, the CAR T cells in current development are not “off-the-shelf” products, but instead are patient-specific and require unique resources for manufacturing. Therefore, proof-of-concept trials have been limited to select centers that have (1) a good manufacturing practice (GMP) facility capable of clinical grade CAR T cell manufacturing and associated quality assessment (QA) and quality control (QC) testing; (2) a vector production facility; and (3) an established clinical cellular therapy program. Second, unlike the development of drugs such as rituximab, where the same molecule was tested identically across centers, not all of the CD19 CAR T cell products clinically tested are alike. Even though the target is the same, each “home grown” CD19-specific CAR differs significantly across centers in (1) the construct used (target binding moiety, structural components, activating endodomains, etc.); (2) the genetic transfer process used for production (lentivirus, retrovirus, or electroporation); (3) the composition of the infused product (dose and phenotype); and (4) trial design (type and doses of conditioning used, management of treatment-related toxicities, etc.). Lastly, from these early trials, it quickly has become apparent that traditional pharmacokinetic studies, which typically assist with determining dosage, need to be replaced with less standardized and more ambiguous metrics, such as T cell expansion, persistence, and functional assays. Locke et al.4Locke F.L. Neelapu S.S. Bartlett N. Siddiqi T. Chavez J.C. Hosing C.M. Ghobadi A. Budde L.E. Bot A. Rossi J.M. et al.Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma.Mol Ther. 2016; 25 (this issue): 285-295Abstract Full Text Full Text PDF Scopus (404) Google Scholar have successfully addressed some of these challenges toward commercialization. Although the safety of their CAR construct has been established at the National Cancer Institute (NCI), where it was originally developed,1Kochenderfer J.N. Dudley M.E. Kassim S.H. Somerville R.P.T. Carpenter R.O. Stetler-Stevenson M. Yang J.C. Phan G.Q. Hughes M.S. Sherry R.M. et al.Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor.J. Clin. Oncol. 2015; 33: 540-549Crossref PubMed Scopus (1194) Google Scholar the primary objective of the current study was to reproduce its safety profile in a multicenter study using cryo-shipped products. In line with now well-established CD19 CAR T cell-related adverse events (AEs), six of seven patients developed cytokine release syndrome (CRS), neurological toxicity, and/or B cell aplasia (the latter being seen in the three patients with continued CAR persistence and long-term remission). Except for one patient, all treatment- related AEs were grade 3 or less and completely resolved within 30 days of treatment. The single patient with a fatal event (death from intracranial bleed) also had bacterial sepsis and sepsis-related thrombocytopenia as major coexisting conditions, making any association with the T cell treatment less likely. Thus, of seven patients treated on this study across four centers, only one patient experienced a dose-limiting toxicity (DLT), meeting the primary safety end-point of the first phase of their study (DLT rate ≤ one in six). Impressively, five out of the seven patients experienced a clinical response, with three having complete remissions that are ongoing over 12 months, which is comparable to the CR rate (four of seven) seen in DLBCL patients in the original NCI study. The authors also demonstrated the feasibility of manufacturing clinical grade T cell products at a central GMP from apheresis units collected from patients across different centers (Figure 1). This uniform manufacturing platform meant that all products were subject to the same manipulation (identical CAR constructs transduced with the same retroviral master line), and an attempt was made to make the same dose of CAR transduced T cells (2 × 106 cells/kg). Products were cryo-shipped to the patient’s centers in a timely fashion (by 2 weeks after procurement). At all four centers, the patients received the same regimen of lymphodepleting cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days prior to T cell infusion. Patients remained hospitalized for 7 days after T cell administration and were monitored for treatment-related AEs with a uniform protocol that specified triggers for treatment with tocilizumab, steroids, or a higher level of care. While we await a truly off-the-shelf universal T cell product, patient-specific CD19-CAR T cells will have to be manufactured on demand in a viable time frame. This work reports one way to streamline manufacturing that allows access to CD19 CAR T cell therapy at several institutions simultaneously. Larger trials are still needed to confirm effectiveness, and the rates and degree of toxicity seen therein are likely going to influence the dose, timing, and patient choice. Additionally, how CAR T cell treatment will be priced given the complexity of manufacturing and the potential for being a “one and done therapy” also remains to be seen. The work by Locke et al.4Locke F.L. Neelapu S.S. Bartlett N. Siddiqi T. Chavez J.C. Hosing C.M. Ghobadi A. Budde L.E. Bot A. Rossi J.M. et al.Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma.Mol Ther. 2016; 25 (this issue): 285-295Abstract Full Text Full Text PDF Scopus (404) Google Scholar is notable for being the first chapter of the next CAR T cell story: “toward FDA approval.” P.L. and C.A.R. have no conflicts of interest to disclose. The Center for Cell and Gene Therapy has a research collaboration with Bluebird Bio and Celgene. P.L. and C.A.R. receive support from NIH grant P50CA126752 (SPORE in LYMPHOMA). P.L. also receives grant support from Leukemia Texas, the ASBMT Young Investigator Award, the Caroline Wiess Law Fund for Research in Molecular Medicine, and the L.E. and Josephine S. Gordy Memorial Cancer Research Fund. C.A.R. also receives grant support from Leukemia Lymphoma Society SCOR award 7018. Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive LymphomaLocke et al.Molecular TherapyDecember 9, 2016In BriefIn a multicenter phase 1 study, Locke, Neelapu, et al. report tolerability and safety of KTE-C19, a CD19 chimeric antigen receptor technology, in patients with chemorefractory DLBCL. More importantly, KTE-C19 could provide durable clinical benefit in this difficult-to-treat patient population, demonstrating broad clinical applicability of KTE-C19. Full-Text PDF Open Access