Scaling up and scaling out: Advances and challenges in manufacturing engineered T cell therapies

References

• Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314(5796):126–129. doi:10.1126/science.1129003.
   PubMed Web of Science ®Google Scholar
• Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917–924. doi:10.1200/JCO.2010.32.2537.
   PubMed Web of Science ®Google Scholar
• Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544. doi:10.1056/NEJMoa1707447.
   PubMed Web of Science ®Google Scholar
• Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–733. doi:10.1056/NEJMoa1103849.
   PubMed Web of Science ®Google Scholar
• Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–1517. doi:10.1056/NEJMoa1407222.
   PubMed Web of Science ®Google Scholar
• Cherkassky L, Morello A, Villena-Vargas J, et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016;126(8):3130–3144. doi:10.1172/JCI83092.
   PubMed Web of Science ®Google Scholar
• Grosser R, Cherkassky L, Chintala N, et al. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell. 2019;36(5):471–482. doi:10.1016/j.ccell.2019.09.006.
   PubMed Web of Science ®Google Scholar
• Roselli E, Faramand R, Davila ML. Insight into next-generation CAR therapeutics: designing CAR T cells to improve clinical outcomes. The Journal of Clinical Investigation. 2021;131(2):e142030. doi:10.1172/JCI142030.
   PubMed Web of Science ®Google Scholar
• Li C, Mei H, Hu Y. Applications and explorations of CRISPR/Cas9 in CAR T-cell therapy. Brief Funct Genomics. 2020;19(3):175–182. doi:10.1093/bfgp/elz042.
   PubMed Web of Science ®Google Scholar
• Pinte L, Cunningham A, Trébéden-Negre H, et al. Global perspective on the development of genetically modified immune cells for cancer therapy. Front Immunol. 2020;11:608485.
   PubMed Web of Science ®Google Scholar
• Zhang J, Wang L. The emerging world of TCR-T cell trials against cancer: a systematic review. Technol Cancer Res Treat. 2019;18:1533033819831068.
   Web of Science ®Google Scholar
• Jin J, Gkitsas N, Fellowes VS, et al. Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules. J Transl Med. 2018;16(1):13. doi:10.1186/s12967-018-1384-z.
   PubMedGoogle Scholar
• Shah NN, Highfill SL, Shalabi H, et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-cell trial. J Clin Oncol. 2020;38(17):1938–1950. doi:10.1200/JCO.19.03279.
   PubMed Web of Science ®Google Scholar
• Sabatino M, Hu J, Sommariva M, et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood. 2016;128(4):519–528. doi:10.1182/blood-2015-11-683847.
   PubMed Web of Science ®Google Scholar
• Jones M, Nankervis B, Roballo KS, et al. A comparison of automated perfusion- and manual diffusion-based human regulatory T cell expansion and functionality using a soluble activator complex. Cell Transplant. 2020;29:963689720923578.
   PubMed Web of Science ®Google Scholar
• Smith TA. CAR-T cell expansion in a Xuri cell expansion system W25. In: Swiech K, Malmegrim KCR, Picanço-Castro V, eds. Chimeric antigen receptor T cells: development and production. New York, NY: Springer US; 2020:151–163.
   Google Scholar
• Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–1518. doi:10.1056/NEJMoa1215134.
   PubMed Web of Science ®Google Scholar
• Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817–4828. doi:10.1182/blood-2011-04-348540.
   PubMed Web of Science ®Google Scholar
• Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38.
   PubMed Web of Science ®Google Scholar
• Coeshott C, Vang B, Jones M, et al. Large-scale expansion and characterization of CD3+ T-cells in the Quantum® Cell Expansion System. J Transl Med. 2019;17(1):258. doi:10.1186/s12967-019-2001-5.
   PubMed Web of Science ®Google Scholar
• Lock D, Mockel-Tenbrinck N, Drechsel K, et al. Automated manufacturing of potent CD20-directed chimeric antigen receptor T cells for clinical use. Hum Gene Ther. 2017;28(10):914–925. doi:10.1089/hum.2017.111.
   PubMed Web of Science ®Google Scholar
• Vedvyas Y, McCloskey JE, Yang Y, et al. Manufacturing and preclinical validation of CAR T cells targeting ICAM-1 for advanced thyroid cancer therapy. Sci Rep. 2019;9(1):10634. doi:10.1038/s41598-019-46938-7.
   PubMedGoogle Scholar
• Shah NN, Johnson BD, Schneider D, 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. doi:10.1038/s41591-020-1081-3.
   PubMed Web of Science ®Google Scholar
• Spiegel JY, Patel S, Muffly L, 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. doi:10.1038/s41591-021-01436-0.
   PubMed Web of Science ®Google Scholar
• Remley VA, Jin J, Sarkar S, et al. High efficiency closed-system gene transfer using automated spinoculation. J Transl Med. 2021;19(1):474. doi:10.1186/s12967-021-03126-4.
   PubMed Web of Science ®Google Scholar
• Li L, Allen C, Shivakumar R, et al. Large volume flow electroporation of mRNA: clinical scale process. Methods Mol Biol. 2013;969:127–138.
   PubMedGoogle Scholar
• Beatty GL, Haas AR, Maus MV, et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol Res. 2014;2(2):112–120. doi:10.1158/2326-6066.CIR-13-0170.
   PubMed Web of Science ®Google Scholar
• Beatty GL, O’Hara MH, Lacey SF, et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology. 2018;155(1):29–32. doi:10.1053/j.gastro.2018.03.029.
   PubMed Web of Science ®Google Scholar
• Tchou J, Zhao Y, Levine BL, et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol Res. 2017;5(12):1152–1161. doi:10.1158/2326-6066.CIR-17-0189.
   PubMed Web of Science ®Google Scholar
• Shah PD, Huang ACC, Xu X, et al. Phase I trial of autologous cMET-directed CAR-t cells administered intravenously in patients with melanoma & breast carcinoma. JCO. 2020;38(15_suppl):10035–10035. doi:10.1200/JCO.2020.38.15_suppl.10035.
   Web of Science ®Google Scholar
• Choi S, Pegues MA, Lam N, et al. Design and assessment of novel anti-CD30 chimeric antigen receptors with human antigen-recognition domains. Hum Gene Ther. 2021;32(13–14):730–743. doi:10.1089/hum.2020.215.
   PubMed Web of Science ®Google Scholar
• Jin BY, Campbell TE, Draper LM, et al. Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight. 2018;3(8) doi:10.1172/jci.insight.99488.
   Web of Science ®Google Scholar
• Nagarsheth NB, Norberg SM, Sinkoe AL, et al. TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021;27(3):419–425. doi:10.1038/s41591-020-01225-1.
   PubMed Web of Science ®Google Scholar
• Fraietta JA, Lacey SF, Orlando EJ, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018;24(5):563–571. doi:10.1038/s41591-018-0010-1.
   PubMed Web of Science ®Google Scholar
• Abou-El-Enein M, Elsallab M, Feldman SA, et al. Scalable manufacturing of CAR T cells for cancer immunotherapy. Blood Cancer Discov. 2021;2(5):408–422. doi:10.1158/2643-3230.BCD-21-0084.
   PubMedGoogle Scholar
• Yang J, He J, Zhang X, et al. A feasibility and safety study of a new CD19-directed fast CAR-T therapy for refractory and relapsed B cell acute lymphoblastic leukemia. Blood. 2019;134(Supplement_1):825–825. doi:10.1182/blood-2019-121751.
   Google Scholar
• Zhang C, He J, Liu L, et al. CD19-directed fast CART therapy for relapsed/refractory acute lymphoblastic leukemia: from bench to bedside. Blood. 2019;134(Supplement_1):1340–1340. doi:10.1182/blood-2019-128006.
   Google Scholar
• Bai Z, Lundh S, Kim D, et al. Single-cell multiomics dissection of basal and antigen-specific activation states of CD19-targeted CAR T cells. J Immunother Cancer. 2021;9(5):e002328. doi:10.1136/jitc-2020-002328.
   PubMed Web of Science ®Google Scholar
• Blaeschke F, Stenger D, Kaeuferle T, et al. Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia. Cancer Immunol Immunother. 2018;67(7):1053–1066. doi:10.1007/s00262-018-2155-7.
   PubMed Web of Science ®Google Scholar