Scaling Up and Scaling Out: Advances and Challenges in Manufacturing Engineered T Cell Therapies

Overview

Journal Int Rev Immunol

Publisher Informa Healthcare

Specialty Allergy & Immunology

Date 2022 Apr 29

PMID 35486592

Authors

Hannah W Song

Robert P Somerville

David F Stroncek

Steven L Highfill

Affiliations

Soon will be listed here.

Abstract

Engineered T cell therapies such as CAR-T cells and TCR-T cells have generated impressive patient responses in previously incurable diseases. In the past few years there have been a number of technical innovations that enable robust clinical manufacturing in functionally closed and often automated systems. Here we describe the latest technology used to manufacture CAR- and TCR-engineered T cells in the clinic, including cell purification, transduction/transfection, expansion and harvest. To help compare the different systems available, we present three case studies of engineered T cells manufactured for phase I clinical trials at the NIH Clinical Center (CD30 CAR-T cells for lymphoma, CD19/CD22 bispecific CAR-T cells for B cell malignancies, and E7 TCR T cells for human papilloma virus-associated cancers). Continued improvement in cell manufacturing technology will help enable world-wide implementation of engineered T cell therapies.

Citing Articles

Current advancements in cellular immunotherapy for autoimmune disease.

Berry C, Frazee C, Herman P, Chen S, Chen A, Kuo Y Semin Immunopathol. 2025; 47(1):7.

PMID: 39821376 PMC: 11739237. DOI: 10.1007/s00281-024-01034-5.

Targeting cancer with precision: strategical insights into TCR-engineered T cell therapies.

Lin P, Lin Y, Mai Z, Zheng Y, Zheng J, Zhou Z Theranostics. 2025; 15(1):300-323.

PMID: 39744228 PMC: 11667231. DOI: 10.7150/thno.104594.

Efficient manufacturing of CAR-T cells from whole blood: a scalable approach to reduce costs and enhance accessibility in cancer therapy.

Traynor R, Vignola I, Sarkar S, Prochazkova M, Cai Y, Shi R Cytotherapy. 2024; 27(3):400-409.

PMID: 39652017 PMC: 11810577. DOI: 10.1016/j.jcyt.2024.11.013.

Metabolic engineering for optimized CAR-T cell therapy.

McPhedran S, Carleton G, Lum J Nat Metab. 2024; 6(3):396-408.

PMID: 38388705 DOI: 10.1038/s42255-024-00976-2.

Manufacture of CD22 CAR T cells following positive versus negative selection results in distinct cytokine secretion profiles and γδ T cell output.

Song H, Benzaoui M, Dwivedi A, Underwood S, Shao L, Achar S Mol Ther Methods Clin Dev. 2024; 32(1):101171.

PMID: 38298420 PMC: 10827561. DOI: 10.1016/j.omtm.2023.101171.

References

Brentjens R, Riviere I, Park J, Davila M, Wang X, Stefanski J . 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):4817-28. PMC: 3208293. DOI: 10.1182/blood-2011-04-348540. View

Zhang J, Wang L . The Emerging World of TCR-T Cell Trials Against Cancer: A Systematic Review. Technol Cancer Res Treat. 2019; 18:1533033819831068. PMC: 6391541. DOI: 10.1177/1533033819831068. View

Cherkassky L, Morello A, Villena-Vargas J, Feng Y, Dimitrov D, Jones D . Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest. 2016; 126(8):3130-44. PMC: 4966328. DOI: 10.1172/JCI83092. View

Fraietta J, Lacey S, Orlando E, Pruteanu-Malinici I, Gohil M, Lundh S . 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. PMC: 6117613. DOI: 10.1038/s41591-018-0010-1. View

Coeshott C, Vang B, Jones M, Nankervis B . Large-scale expansion and characterization of CD3 T-cells in the Quantum Cell Expansion System. J Transl Med. 2019; 17(1):258. PMC: 6686483. DOI: 10.1186/s12967-019-2001-5. View

Jin B, Campbell T, Draper L, Stevanovic S, Weissbrich B, Yu Z . Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. JCI Insight. 2018; 3(8). PMC: 5931134. DOI: 10.1172/jci.insight.99488. View

Pinte L, Cunningham A, Trebeden-Negre H, Nikiforow S, Ritz J . Global Perspective on the Development of Genetically Modified Immune Cells for Cancer Therapy. Front Immunol. 2021; 11:608485. PMC: 7917113. DOI: 10.3389/fimmu.2020.608485. View

Porter D, Levine B, Kalos M, Bagg A, June C . Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011; 365(8):725-33. PMC: 3387277. DOI: 10.1056/NEJMoa1103849. View

Shah N, Johnson B, Schneider D, Zhu F, Szabo A, Keever-Taylor C . 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. View

10.

Shah P, Huang A, Xu X, Orlowski R, Amaravadi R, Schuchter L . Phase I Trial of Autologous RNA-electroporated cMET-directed CAR T Cells Administered Intravenously in Patients with Melanoma and Breast Carcinoma. Cancer Res Commun. 2023; 3(5):821-829. PMC: 10167933. DOI: 10.1158/2767-9764.CRC-22-0486. View

11.

Robbins P, Morgan R, Feldman S, Yang J, Sherry R, Dudley M . 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):917-24. PMC: 3068063. DOI: 10.1200/JCO.2010.32.2537. View

12.

Nagarsheth N, Norberg S, Sinkoe A, Adhikary S, Meyer T, Lack J . TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers. Nat Med. 2021; 27(3):419-425. PMC: 9620481. DOI: 10.1038/s41591-020-01225-1. View

13.

Maude S, Frey N, Shaw P, Aplenc R, Barrett D, Bunin N . Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014; 371(16):1507-17. PMC: 4267531. DOI: 10.1056/NEJMoa1407222. View

14.

Jin J, Gkitsas N, Fellowes V, Ren J, Feldman S, Hinrichs C . Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules. J Transl Med. 2018; 16(1):13. PMC: 5784598. DOI: 10.1186/s12967-018-1384-z. View

15.

Abou-El-Enein M, Elsallab M, Feldman S, Fesnak A, Heslop H, Marks P . Scalable Manufacturing of CAR T cells for Cancer Immunotherapy. Blood Cancer Discov. 2021; 2(5):408-422. PMC: 8462122. DOI: 10.1158/2643-3230.BCD-21-0084. View

16.

Bai Z, Lundh S, Kim D, Woodhouse S, Barrett D, Myers R . Single-cell multiomics dissection of basal and antigen-specific activation states of CD19-targeted CAR T cells. J Immunother Cancer. 2021; 9(5). PMC: 8137188. DOI: 10.1136/jitc-2020-002328. View

17.

Jones M, Nankervis B, Roballo K, Pham H, Bushman J, Coeshott C . 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. PMC: 7586259. DOI: 10.1177/0963689720923578. View

18.

Beatty G, OHara M, Lacey S, Torigian D, Nazimuddin F, Chen F . Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial. Gastroenterology. 2018; 155(1):29-32. PMC: 6035088. DOI: 10.1053/j.gastro.2018.03.029. View

19.

Brentjens R, Davila M, Riviere I, Park J, Wang X, Cowell L . CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013; 5(177):177ra38. PMC: 3742551. DOI: 10.1126/scitranslmed.3005930. View

20.

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. PMC: 7239310. DOI: 10.1093/bfgp/elz042. View