Technological and Manufacturing Innovation Drive Improved Access to Engineered T Cell Therapies
Main Article Content
Abstract
The creation of autologous gene-modified cell products, such as CAR-T cells (chimeric antigen receptor T cells) has met with clinical success but has been severely restricted by cost, availability, and current commercial models of central manufacturing. Moreover, the inability to produce CAR-T cells at reasonable cost in all but the largest centers slow innovation. CAR-T cells are unique in that these ex vivo expanded effector T cell populations express activation receptors comprised of immunoglobulin-like binders, or other immune ligands, bypassing the restriction of expanding and appropriately activating effector cells that arise by recombination of V-D-J genetic elements. However, the use of a single binding moiety to recognize leukemia target cells has selected for the generation of escape mutants, or for cryptic clones to expand that were not initially detected upon diagnostic work-up. To meet this challenge, we have engineered both B cell malignancy-specific and HIV surface antigen-specific CAR-T cells that express multiple binding moieties, thereby reducing the chance of immune escape. The creation of a therapeutic CAR-T cell population also requires a complex set of procedures that includes procurement of a large number of patient T cells, most often by leukapheresis, activation of the T cell population using matrix-associated antibodies targeting the T cell receptor and an immune co-receptor, a gene vector to permanently transduce T cells, and a bioreactor that can accommodate the expansion of the engineered cell population to numbers suitable for infusion. This complex set of procedures, combined with the current central processing model, has led to a complex chain of custody and expensive temperature-controlled shipping requirements. We present here a model whereby production of CAR-T cells at the point of care, using simplified cell procurement, purification, and expansion, can reduce the time and expense of CAR-T cell generation, with the aim to expand the use of these therapies in both the majority world, and in managed care or publicly funded systems. The CAR-T populations produced in this point-of-care ready process are highly active, viable, and have preferred CAR-T phenotypic characteristics associated with clinical efficacy.
Article Details
How to Cite
XIONG, Ying et al.
Technological and Manufacturing Innovation Drive Improved Access to Engineered T Cell Therapies.
Medical Research Archives, [S.l.], v. 11, n. 11, nov. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4759>. Date accessed: 16 may 2024.
doi: https://doi.org/10.18103/mra.v11i11.4759.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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28. Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016; 126(6): 2123-2138. e-pub ahead of print 20160425; doi: 10.1172/JCI85309
29. Castella M, Boronat A, Martin-Ibanez R, Rodriguez V, Sune G, Caballero M et al. Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions. Mol Ther Methods Clin Dev 2019; 12: 134-144. e-pub ahead of print 20181206;
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30. Ortiz-Maldonado V, Rives S, Castella M, Alonso-Saladrigues A, Benitez-Ribas D, Caballero-Banos M et al. CART19-BE-01: A Multicenter Trial of ARI-0001 Cell Therapy in Patients with CD19(+) Relapsed/Refractory Malignancies. Mol Ther 2021; 29(2): 636-644. e-pub ahead of print 20200920; doi: 10.1016/j.ymthe.2020.09.027
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33. Korell F, Laier S, Sauer S, Veelken K, Hennemann H, Schubert ML et al. Current Challenges in Providing Good Leukapheresis Products for Manufacturing of CAR-T Cells for Patients with Relapsed/Refractory NHL or ALL. Cells 2020; 9(5). e-pub ahead of print 20200515; doi: 10.3390/cells9051225
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36. Derman BA, Nikiforow S, Im S-Y, Ikegawa S, Prabhala RH, Rodriguez DH et al. Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM). Journal of Clinical Oncology 2023; 41(16_suppl): 8004-8004. doi: 10.1200/JCO.2023.41.16_suppl.8004
37. Mussetti A, Sureda A. Second-line CAR T cells for lymphomas. Lancet 2022; 399(10343): 2247-2249. doi: 10.1016/S0140-6736(22)00790-5
38. Westin J, Sehn LH. CAR T cells as a second-line therapy for large B-cell lymphoma: a paradigm shift? Blood 2022; 139(18): 2737-2746. doi: 10.1182/blood.2022015789
2. Mei MG, Chen L, Godfrey J, Song JY, Egelston C, Budde LE et al. Pembrolizumab plus vorinostat is highly active in Hodgkin lymphoma, including patients refractory to prior PD-1 blockade. Blood 2023. e-pub ahead of print 20230620;
doi: 10.1182/blood.2023020485
3. Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol 2019; 16(6): 372-385. doi: 10.1038/s41571-019-0184-6
4. Tseng A, Seet J, Phillips EJ. The evolution of three decades of antiretroviral therapy: challenges, triumphs and the promise of the future. Br J Clin Pharmacol 2015; 79(2): 182-194. doi: 10.1111/bcp.12403
5. Halim L, Maher J. CAR T-cell immunotherapy of B-cell malignancy: the story so far. Ther Adv Vaccines Immunother 2020; 8: 2515135520927164. e-pub ahead of print 20200527;
doi: 10.1177/2515135520927164
6. Shargian L, Raanani P, Yeshurun M, Gafter-Gvili A, Gurion R. CAR-T cell therapy is superior to standard of care as second-line therapy for large B-cell lymphoma: A systematic review and meta-analysis. Br J Haematol 2023; 200(1): e4-e5. e-pub ahead of print 20221025; doi: 10.1111/bjh.18506
7. Cortes-Lopez M, Schulz L, Enculescu M, Paret C, Spiekermann B, Quesnel-Vallieres M et al. High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance. Nat Commun 2022; 13(1): 5570. e-pub ahead of print 20220922; doi: 10.1038/s41467-022-31818-y
8. Schneider D, Xiong Y, Wu D, Nlle V, Schmitz S, Haso W et al. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J Immunother Cancer 2017; 5: 42. e-pub ahead of print 20170516; doi: 10.1186/s40425-017-0246-1
9. Shah NN, Johnson BD, Schneider D, Zhu F, Szabo A, Keever-Taylor CA 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(10): 1569-1575. e-pub ahead of print 20201005; doi: 10.1038/s41591-020-1081-3
10. Zurko JC, Fenske TS, Johnson BD, Bucklan D, Szabo A, Xu H et al. Long-term outcomes and predictors of early response, late relapse, and survival for patients treated with bispecific LV20.19 CAR T-cells. Am J Hematol 2022; 97(12): 1580-1588. e-pub ahead of print 20220920; doi: 10.1002/ajh.26718
11. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368(16): 1509-1518. e-pub ahead of print 20130325; doi: 10.1056/NEJMoa1215134
12. Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 2013; 121(7): 1165-1174. e-pub ahead of print 20121214; doi: 10.1182/blood-2012-06-438002
13. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 2018; 24(1): 20-28. e-pub ahead of print 20171120; doi: 10.1038/nm.4441
14. Spiegel JY, Patel S, Muffly L, Hossain NM, Oak J, Baird JH et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med 2021; 27(8): 1419-1431. e-pub ahead of print 20210726; doi: 10.1038/s41591-021-01436-0
15. Kokalaki E, Ma B, Ferrari M, Grothier T, Hazelton W, Manzoor S et al. Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR. Mol Ther 2023; 31(7): 2089-2104. e-pub ahead of print 20230321;
doi: 10.1016/j.ymthe.2023.03.020
16. Shalabi H, Qin H, Su A, Yates B, Wolters PL, Steinberg SM et al. CD19/22 CAR T cells in children and young adults with B-ALL: phase 1 results and development of a novel bicistronic CAR. Blood 2022; 140(5): 451-463. doi: 10.1182/blood.2022015795
17. Schneider D, Xiong Y, Wu D, Hu P, Alabanza L, Steimle B et al. Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. Sci Transl Med 2021; 13(586). doi: 10.1126/scitranslmed.abc6401
18. Anthony-Gonda K, Bardhi A, Ray A, Flerin N, Li M, Chen W et al. Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model. Sci Transl Med 2019; 11(504). doi: 10.1126/scitranslmed.aav5685
19. Anthony-Gonda K, Ray A, Su H, Wang Y, Xiong Y, Lee D et al. In vivo killing of primary HIV-infected cells by peripheral-injected early memory-enriched anti-HIV duoCAR T cells. JCI Insight 2022; 7(21). e-pub ahead of print 20221108; doi: 10.1172/jci.insight.161698
20. Mikhael J, Fowler J, Shah N. Chimeric Antigen Receptor T-Cell Therapies: Barriers and Solutions to Access. JCO Oncol Pract 2022; 18(12): 800-807. e-pub ahead of print 20220921; doi: 10.1200/OP.22.00315
21. Geethakumari PR, Ramasamy DP, Dholaria B, Berdeja J, Kansagra A. Balancing Quality, Cost, and Access During Delivery of Newer Cellular and Immunotherapy Treatments. Curr Hematol Malig Rep 2021; 16(4): 345-356. e-pub ahead of print 20210605; doi: 10.1007/s11899-021-00635-3
22. Emole J, Lawal O, Lupak O, Dias A, Shune L, Yusuf K. Demographic differences among patients treated with chimeric antigen receptor T-cell therapy in the United States. Cancer Med 2022; 11(23): 4440-4448. e-pub ahead of print 20220508; doi: 10.1002/cam4.4797
23. Adair JE, Androski L, Bayigga L, Bazira D, Brandon E, Dee L et al. Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI). Gene Ther 2021. e-pub ahead of print 20210908; doi: 10.1038/s41434-021-00284-4
24. Orentas RJ, Dropulic B, de Lima M. Place of care manufacturing of chimeric antigen receptor cells: Opportunities and challenges. Semin Hematol 2023; 60(1): 20-24. e-pub ahead of print 20230124; doi: 10.1053/j.seminhematol.2023.01.001
25. Kaiser AD, Assenmacher M, Schroder B, Meyer M, Orentas R, Bethke U et al. Towards a commercial process for the manufacture of genetically modified T cells for therapy. Cancer Gene Ther 2015; 22(2): 72-78. e-pub ahead of print 20150123; doi: 10.1038/cgt.2014.78
26. Palani HK, Arunachalam AK, Yasar M, Venkatraman A, Kulkarni U, Lionel SA et al. Decentralized manufacturing of anti CD19 CAR-T cells using CliniMACS Prodigy(R): real-world experience and cost analysis in India. Bone Marrow Transplant 2023; 58(2): 160-167. e-pub ahead of print 20221108; doi: 10.1038/s41409-022-01866-5
27. Long AH, Haso WM, Shern JF, Wanhainen KM, Murgai M, Ingaramo M et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 2015; 21(6): 581-590. e-pub ahead of print 20150504; doi: 10.1038/nm.3838
28. Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest 2016; 126(6): 2123-2138. e-pub ahead of print 20160425; doi: 10.1172/JCI85309
29. Castella M, Boronat A, Martin-Ibanez R, Rodriguez V, Sune G, Caballero M et al. Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions. Mol Ther Methods Clin Dev 2019; 12: 134-144. e-pub ahead of print 20181206;
doi: 10.1016/j.omtm.2018.11.010
30. Ortiz-Maldonado V, Rives S, Castella M, Alonso-Saladrigues A, Benitez-Ribas D, Caballero-Banos M et al. CART19-BE-01: A Multicenter Trial of ARI-0001 Cell Therapy in Patients with CD19(+) Relapsed/Refractory Malignancies. Mol Ther 2021; 29(2): 636-644. e-pub ahead of print 20200920; doi: 10.1016/j.ymthe.2020.09.027
31. Castella M, Caballero-Banos M, Ortiz-Maldonado V, Gonzalez-Navarro EA, Sune G, Antonana-Vidosola A et al. Point-Of-Care CAR T-Cell Production (ARI-0001) Using a Closed Semi-automatic Bioreactor: Experience From an Academic Phase I Clinical Trial. Front Immunol 2020; 11: 482. e-pub ahead of print 20200320; doi: 10.3389/fimmu.2020.00482
32. So EC, Sallin MA, Zhang X, Chan SL, Sahni L, Schulze DH et al. A high throughput method for enrichment of natural killer cells and lymphocytes and assessment of in vitro cytotoxicity. J Immunol Methods 2013; 394(1-2): 40-48. e-pub ahead of print 20130513; doi: 10.1016/j.jim.2013.05.001
33. Korell F, Laier S, Sauer S, Veelken K, Hennemann H, Schubert ML et al. Current Challenges in Providing Good Leukapheresis Products for Manufacturing of CAR-T Cells for Patients with Relapsed/Refractory NHL or ALL. Cells 2020; 9(5). e-pub ahead of print 20200515; doi: 10.3390/cells9051225
34. Ghassemi S, Durgin JS, Nunez-Cruz S, Patel J, Leferovich J, Pinzone M et al. Rapid manufacturing of non-activated potent CAR T cells. Nat Biomed Eng 2022; 6(2): 118-128. e-pub ahead of print 20220221; doi: 10.1038/s41551-021-00842-6
35. Flinn IW, Jaeger U, Shah NN, Blaise D, Briones J, Shune L et al. A First-in-Human Study of YTB323, a Novel, Autologous CD19-Directed CAR-T Cell Therapy Manufactured Using the Novel T-Charge TM platform, for the Treatment of Patients (Pts) with Relapsed/Refractory (r/r) Diffuse Large B-Cell Lymphoma (DLBCL). Blood 2021; 138(Supplement 1): 740-740. doi: 10.1182/blood-2021-146268
36. Derman BA, Nikiforow S, Im S-Y, Ikegawa S, Prabhala RH, Rodriguez DH et al. Updated phase I study results of PHE885, a T-Charge manufactured BCMA-directed CAR-T cell therapy, for patients (pts) with r/r multiple myeloma (RRMM). Journal of Clinical Oncology 2023; 41(16_suppl): 8004-8004. doi: 10.1200/JCO.2023.41.16_suppl.8004
37. Mussetti A, Sureda A. Second-line CAR T cells for lymphomas. Lancet 2022; 399(10343): 2247-2249. doi: 10.1016/S0140-6736(22)00790-5
38. Westin J, Sehn LH. CAR T cells as a second-line therapy for large B-cell lymphoma: a paradigm shift? Blood 2022; 139(18): 2737-2746. doi: 10.1182/blood.2022015789