CD28 costimulation improves expansion and persistence of chimeric antigen receptor–modified T cells in lymphoma patients
Open accessAbstract
Targeted T cell immunotherapies using engineered T lymphocytes expressing tumor-directed chimeric antigen receptors (CARs) are designed to benefit patients with cancer. Although incorporation of costimulatory endodomains within these CARs increases the proliferation of CAR-redirected T lymphocytes, it has proven difficult to draw definitive conclusions about the specific effects of costimulatory endodomains on the expansion, persistence, and antitumor effectiveness of CAR-redirected T cells in human subjects, owing to the lack of side-by-side comparisons with T cells bearing only a single signaling domain. We therefore designed a study that allowed us to directly measure the consequences of adding a costimulatory endodomain to CAR-redirected T cells. Patients with B cell lymphomas were simultaneously infused with 2 autologous T cell products expressing CARs with the same specificity for the CD19 antigen, present on most B cell malignancies. One CAR encoded both the costimulatory CD28 and the ζ-endodomains, while the other encoded only the ζ-endodomain. CAR+ T cells containing the CD28 endodomain showed strikingly enhanced expansion and persistence compared with CAR+ T cells lacking this endodomain. These results demonstrate the superiority of CARs with dual signal domains and confirm a method of comparing CAR-modified T cells within individual patients, thereby avoiding patient-to-patient variability and accelerating the development of optimal T cell immunotherapies.
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Most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing.
“First, most CAR T cell trials to date have used autologous peripheral blood and apheresis as the main cell sources for manufacturing (9-18,21,22).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [15]
All approved CAR T-cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) co-stimulatory signals.
“All approved CAR T-cell products are second-generation CARs that incorporate CD28 or CD137 (4-1BB) co-stimulatory signals, which are essential for eliciting effector and memory cell expansion and persistence and a clinically relevant immune response (9-15).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [15]
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- Authors
- Savoldo, B., Ramos, C. A., Liu, E., Mims, M. P., Keating, M. J., Carrum, G., Kamble, R. T., Bollard, C. M., Gee, A. P., Mei, Z., Liu, H., Grilley, B., Rooney, C. M., Heslop, H. E., Brenner, M. K., & Dotti, G.
- Affiliations
- Baylor College of Medicine (US)
- Houston Methodist (US)
- The University of Texas MD Anderson Cancer Center (US)
- Dan L Duncan Comprehensive Cancer Center (US)
- Corresponding author
- Dotti, Gianpietro
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-05-02
- Volume
- 121
- Issue
- 5
- Pages
- 1822-1826
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3083795
- OpenAlex
- W2076991609
- Cited by
- 1,023
- References
- 0
- Citations by year
- 2026: 29 · 2025: 38 · 2024: 43 · 2023: 73 · 2022: 58 · 2021: 67 · 2020: 70 · 2019: 84 · 2018: 99 · 2017: 98 · 2016: 81 · 2015: 88 · 2014: 56 · 2013: 75 · 2012: 38
- FWCI
- 30.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- Leukemia and Lymphoma Society
- National Cancer Institute (P01CA094237, P30CA125123, P50CA126752)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- chimeric antigen receptor T cells, CD28 costimulation, B-cell lymphoma, CD19, T cell expansion, T cell persistence, CAR T-cell therapy
- MeSH terms
- Female, Humans, Immunotherapy, Lymphocyte Activation, Lymphoma, Lymphoma, Non-Hodgkin, Male, Middle Aged, Retroviridae, T-Lymphocytes, Tomography, X-Ray Computed, Immunophenotyping, Lymphoma, B-Cell, Protein Structure, Tertiary, CD28 Antigens, Antigens, CD19, Positron-Emission Tomography
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