Multiple site place-of-care manufactured anti-CD19 CAR-T cells induce high remission rates in B-cell malignancy patients
Michael Maschan, Paolo F Caimi, Jane Reese-Koc, Gabriela Pacheco Sanchez, Ashish A Sharma, Olga Molostova, Larisa Shelikhova, Dmitriy Pershin, Alexey Stepanov, Yakov Muzalevskii, Vinicius G Suzart, Folashade Otegbeye, David Wald, Ying Xiong, Darong Wu, Adam Knight, Ibe Oparaocha, Beatrix Ferencz, Andre Roy, Andrew Worden, Winfried Kruger, Michael Kadan, Dina Schneider, Rimas Orentas, Rafick-Pierre Sekaly, Marcos de Lima, Boro Dropulić, Michael Maschan, Paolo F Caimi, Jane Reese-Koc, Gabriela Pacheco Sanchez, Ashish A Sharma, Olga Molostova, Larisa Shelikhova, Dmitriy Pershin, Alexey Stepanov, Yakov Muzalevskii, Vinicius G Suzart, Folashade Otegbeye, David Wald, Ying Xiong, Darong Wu, Adam Knight, Ibe Oparaocha, Beatrix Ferencz, Andre Roy, Andrew Worden, Winfried Kruger, Michael Kadan, Dina Schneider, Rimas Orentas, Rafick-Pierre Sekaly, Marcos de Lima, Boro Dropulić
Abstract
Chimeric antigen receptor (CAR) T cells targeting the CD19 antigen are effective in treating adults and children with B-cell malignancies. Place-of-care manufacturing may improve performance and accessibility by obviating the need to cryopreserve and transport cells to centralized facilities. Here we develop an anti-CD19 CAR (CAR19) comprised of the 4-1BB co-stimulatory and TNFRSF19 transmembrane domains, showing anti-tumor efficacy in an in vivo xenograft lymphoma model. CAR19 T cells are manufactured under current good manufacturing practices (cGMP) at two disparate clinical sites, Moscow (Russia) and Cleveland (USA). The CAR19 T-cells is used to treat patients with relapsed/refractory pediatric B-cell Acute Lymphocytic Leukemia (ALL; n = 31) or adult B-cell Lymphoma (NHL; n = 23) in two independently conducted phase I clinical trials with safety as the primary outcome (NCT03467256 and NCT03434769, respectively). Probability of measurable residual disease-negative remission was also a primary outcome in the ALL study. Secondary outcomes include complete remission (CR) rates, overall survival and median duration of response. CR rates are 89% (ALL) and 73% (NHL). After a median follow-up of 17 months, one-year survival rate of ALL complete responders is 79.2% (95%CI 64.5‒97.2%) and median duration of response is 10.2 months. For NHL complete responders one-year survival is 92.9%, and median duration of response has not been reached. Place-of-care manufacturing produces consistent CAR-T cell products at multiple sites that are effective for the treatment of patients with B-cell malignancies.
Conflict of interest statement
D.S., Y.X., D.W., A.K., W.K., A.W. and M.K. are employees of Lentigen, a MiltenyiBiotec Company. The remaining authors declare no competing interests.
© 2021. The Author(s).
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References
- Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N. Engl. J. Med. 2015;373:1541–1552. doi: 10.1056/NEJMra1400972.
- Ko RH, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J. Clin. Oncol. 2010;28:648–654. doi: 10.1200/JCO.2009.22.2950.
- Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J. Clin. Oncol. 2011;29:551–565. doi: 10.1200/JCO.2010.30.7405.
- Schrappe M, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N. Engl. J. Med. 2012;366:1371–1381. doi: 10.1056/NEJMoa1110169.
- Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125:22–32. doi: 10.1182/blood-2014-05-577189.
- Dunleavy K, Wilson WH. Primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma: do they require a unique therapeutic approach? Blood. 2015;125:33–39. doi: 10.1182/blood-2014-05-575092.
- Casulo C, Burack WR, Friedberg JW. Transformed follicular non-Hodgkin lymphoma. Blood. 2015;125:40–47. doi: 10.1182/blood-2014-04-516815.
- Crump M, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130:1800–1808. doi: 10.1182/blood-2017-03-769620.
- Stamenkovic I, Seed B. CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail. J. Exp. Med. 1988;168:1205–1210. doi: 10.1084/jem.168.3.1205.
- Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk. Lymphoma. 1995;18:385–397. doi: 10.3109/10428199509059636.
- Topp MS, et al. Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J. Clin. Oncol. 2014;32:4134–4140. doi: 10.1200/JCO.2014.56.3247.
- Maude SL. Tisagenlecleucel in pediatric patients with acute lymphoblastic leukemia. Clin. Adv. Hematol. Oncol. 2018;16:664–666.
- Kochenderfer JN, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119:2709–2720. doi: 10.1182/blood-2011-10-384388.
- Kochenderfer JN, 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;33:540–549. doi: 10.1200/JCO.2014.56.2025.
- Turtle CJ, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl. Med. 2016;8:355ra116. doi: 10.1126/scitranslmed.aaf8621.
- Kochenderfer JN, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol. Ther. 2017;25:2245–2253. doi: 10.1016/j.ymthe.2017.07.004.
- Holzinger A, Barden M, Abken H. The growing world of CAR T cell trials: a systematic review. Cancer Immunol., immunotherapy. 2016;65:1433–1450. doi: 10.1007/s00262-016-1895-5.
- Majzner RG, Mackall CL. Clinical lessons learned from the first leg of the CAR T cell journey. Nat. Med. 2019;25:1341–1355. doi: 10.1038/s41591-019-0564-6.
- Schuster SJ, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 2017;377:2545–2554. doi: 10.1056/NEJMoa1708566.
- Neelapu SS, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 2017;377:2531–2544. doi: 10.1056/NEJMoa1707447.
- Schneider D, et al. A unique human immunoglobulin heavy chain variable domain-only CD33 CAR for the treatment of acute myeloid leukemia. Front. Oncol. 2018;8:539. doi: 10.3389/fonc.2018.00539.
- Schneider, D. et al. Transmembrane and linker domain amino acid composition alters chimeric antigen receptor (CAR) membrane residence and may conceal detection of novel functional CAR formats. In 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): Part 1, Vol. 7, 20 (Society for Immunotherapy of Cancer, 2019).
- Gattinoni L, Speiser DE, Lichterfeld M, Bonini C. T memory stem cells in health and disease. Nat. Med. 2017;23:18–27. doi: 10.1038/nm.4241.
- Deng Q, et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat. Med. 2020;26:1878–1887. doi: 10.1038/s41591-020-1061-7.
- Krishna S, et al. Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer. Science. 2020;370:1328–1334. doi: 10.1126/science.abb9847.
- Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70:11–20. doi: 10.1016/j.cyto.2014.05.024.
- Maude SL, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 2014;371:1507–1517. doi: 10.1056/NEJMoa1407222.
- Deng Q, et al. Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat. Med. 2020;26:1878–1887. doi: 10.1038/s41591-020-1061-7.
- Sade-Feldman M, et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell. 2018;175:998–1013 e1020. doi: 10.1016/j.cell.2018.10.038.
- Shah NN, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat. Med. 2020;26:1569–1575. doi: 10.1038/s41591-020-1081-3.
- Schneider D, et al. Trispecific CD19-CD20-CD22–targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci. Transl. Med. 2021;13:eabc6401. doi: 10.1126/scitranslmed.abc6401.
- Gardner RA, et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood. 2019;134:2149–2158. doi: 10.1182/blood.2019001463.
- Kadauke S, et al. Risk-adapted preemptive tocilizumab to prevent severe cytokine release syndrome after CTL019 for pediatric B-cell acute lymphoblastic leukemia: a Prospective Clinical Trial. J. Clin. Oncol. 2021;134:920–930. doi: 10.1200/JCO.20.02477.
- Pasquini MC, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4:5414–5424. doi: 10.1182/bloodadvances.2020003092.
- Abramson JS, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839–852. doi: 10.1016/S0140-6736(20)31366-0.
- Schuster SJ, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 2019;380:45–56. doi: 10.1056/NEJMoa1804980.
- Zhu F, et al. Closed-system manufacturing of CD19 and dual-targeted CD20/19 chimeric antigen receptor T cells using the CliniMACS Prodigy device at an academic medical center. Cytotherapy. 2018;20:394–406. doi: 10.1016/j.jcyt.2017.09.005.
- Jackson Z, et al. Automated manufacture of autologous CD19 CAR-T cells for treatment of non-Hodgkin lymphoma. Front. Immunol. 2020;11:1941. doi: 10.3389/fimmu.2020.01941.
- Lee DW, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–195. doi: 10.1182/blood-2014-05-552729.
- Weintraub S, et al. Cognition assessment using the NIH Toolbox. Neurology. 2013;80:S54–S64. doi: 10.1212/WNL.0b013e3182872ded.
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