CAR-T cell manufacturing: Major process parameters and next-generation strategies

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Abstract

The success of CAR-T cell therapies is dependent on effective cell manufacturing that impacts product safety, efficacy, and patient accessibility. Here, we discuss major process parameters of autologous CAR-T cell manufacturing, regulatory considerations, and emerging technologies in therapeutic cell manufacturing.

Abstract

Chimeric antigen receptor (CAR)-T cell therapies have demonstrated strong curative potential and become a critical component in the array of B-cell malignancy treatments. Successful deployment of CAR-T cell therapies to treat hematologic and solid cancers, as well as other indications such as autoimmune diseases, is dependent on effective CAR-T cell manufacturing that impacts not only product safety and efficacy but also overall accessibility to patients in need. In this review, we discuss the major process parameters of autologous CAR-T cell manufacturing, as well as regulatory considerations and ongoing developments that will enable the next generation of CAR-T cell therapies.

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Most cited references 146

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Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Shannon Maude, Theodore Laetsch, Jochen Buechner … (2018)

In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

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Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Stephen Schuster, Michael R. Bishop, Constantine Tam … (2018)

Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.

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Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study

Jeremy S. Abramson, M. Palomba, Leo I Gordon … (2020)

Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas.

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Author and article information

Contributors

Melanie Ayala Ceja:

ORCID: https://orcid.org/0000-0002-2906-5786

Role: ConceptualizationRole: Data curationRole: InvestigationRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Mobina Khericha:

ORCID: https://orcid.org/0000-0002-6734-7741

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing - original draftRole: Writing - review & editing

Caitlin M. Harris:

ORCID: https://orcid.org/0000-0003-2325-1729

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Cristina Puig-Saus:

ORCID: https://orcid.org/0000-0002-3014-3649

Role: Data curationRole: Writing - original draftRole: Writing - review & editing

Yvonne Y. Chen:

ORCID: https://orcid.org/0000-0002-5583-119X

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J Exp Med

Journal ID (publisher-id): jem

Title: The Journal of Experimental Medicine

Publisher: Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date Collection: 05 February 2024

Publication date (Electronic): 16 January 2024

Publication date PMC-release: 16 January 2024

Volume: 221

Issue: 2

Electronic Location Identifier: e20230903

Affiliations

[1 ]Department of Microbiology, Immunology, and Molecular Genetics, University of California−Los Angeles ( https://ror.org/046rm7j60) , Los Angeles, CA, USA

[2 ]Department of Medicine, University of California−Los Angeles ( https://ror.org/046rm7j60) , Los Angeles, CA, USA

[3 ]Jonsson Comprehensive Cancer Center, University of California−Los Angeles ( https://ror.org/046rm7j60) , Los Angeles, CA, USA

[4 ]Parker Institute for Cancer Immunotherapy Center at University of California−Los Angeles ( https://ror.org/0184qbg02) , Los Angeles, CA, USA

[5 ]Department of Chemical and Biomolecular Engineering, University of California−Los Angeles ( https://ror.org/046rm7j60) , Los Angeles, CA, USA

Author notes

Correspondence to Yvonne Y. Chen: yvchen@ 123456ucla.edu

[*]

M. Khericha and C.M. Harris contributed equally to this paper.

Disclosures: C. Puig-Saus reported personal fees from ImmPACT Bio outside the submitted work; in addition, C. Puig-Saus had a patent to “Targeted replacement of endogenous T cell receptors” licensed to ArsenalBio with royalties paid, and a patent to “Chimeric antigen receptors and related methods and compositions for the treatment of cancer” licensed to ImmPACT Bio with royalties paid. Y.Y. Chen reported personal fees from ImmPACT Bio, Catamaran Bio, Notch Therapeutics, Pluto Immunotherapeutics, Pirme Medicine, Sonoma Biotherapeutics, and Waypoint Bio outside the submitted work; in addition, Y.Y. Chen had a patent to “Cytotoxic molecules responsive to intracellular ligands for selective T cell mediated killing” licensed to ImmPACT Bio with royalties paid, a patent to “Bispecific OR-gate chimeric antigen receptor responsive to CD19 and CD20” licensed to ImmPACT Bio, a patent to US “Transforming growth factor-β-responsive polypeptides and their methods for use” licensed to ImmPACT Bio, a patent to “Chimeric antigen receptors and related methods and compositions for the treatment of cancer” licensed to ImmPACT Bio with royalties paid, a patent to “Methods for making and using therapeutic cells” pending, and a patent to “Single-chain bispecific chimeric antigen receptors for the treatment of cancer” pending. No other disclosures were reported.

Author information

Melanie Ayala Ceja https://orcid.org/0000-0002-2906-5786

Mobina Khericha https://orcid.org/0000-0002-6734-7741

Caitlin M. Harris https://orcid.org/0000-0003-2325-1729

Cristina Puig-Saus https://orcid.org/0000-0002-3014-3649

Yvonne Y. Chen https://orcid.org/0000-0002-5583-119X

Article

Publisher ID: jem.20230903

DOI: 10.1084/jem.20230903

PMC ID: 10791545

PubMed ID: 38226974

SO-VID: 51bd669a-6d7b-4b4a-926c-51f50b7d9bf0

License:

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

History

Date received : 23 October 2023

Date revision received : 02 December 2023

Date accepted : 14 December 2023

Funding

Funded by: California Institute for Regenerative Medicine, DOI http://dx.doi.org/10.13039/100000900;

Award ID: TRAN1-11555

Funded by: Parker Institute for Cancer Immunotherapy, DOI http://dx.doi.org/10.13039/100014547;

CAR-T cell manufacturing: Major process parameters and next-generation strategies

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Most cited references 146

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study

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