Structural Design of Engineered Costimulation Determines Tumor Rejection Kinetics and Persistence of CAR T Cells
Open accessAbstract
T cell engineering is a powerful means to rapidly generate anti-tumor T cells. The costimulatory properties of second-generation chimeric antigen receptors (CARs) determine the overall potency of adoptively transferred T cells. Using an in vivo "stress test" to challenge CD19-targeted T cells, we studied the functionality and persistence imparted by seven different CAR structures providing CD28 and/or 4-1BB costimulation. One configuration, which uses two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand, provided the highest therapeutic efficacy, showing balanced tumoricidal function and increased T cell persistence accompanied by an elevated CD8/CD4 ratio and decreased exhaustion. Remarkably, induction of the IRF7/IFNβ pathway was required for optimal anti-tumor activity. Thus, 1928z-41BBL T cells possess strikingly potent intrinsic and immunomodulatory qualities.
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Efforts to improve functional CAR T cell performance have spawned CAR T cell products co-expressing additional costimulatory receptors.
“Efforts to improve functional CAR T cell performance has spawned CAR T cell products co-expressing additional costimulatory receptors [3,4,5,6], including CD80/CD86-CD28 [3,5], 41BBL-CD137 [6], CD70-CD27 [7], and CD40-CD40L [8], or the constitutive active CD40/TLR4 [9].”
From Ectopic PU.1 Expression Provides Chimeric Antigen Receptor (CAR) T Cells with Innate Cell Capacities Including IFN-β Release (2024) · cites this paper as [6]
The Results describe CAR T-cell configurations that co-express costimulatory ligands, including 4-1BBL or CD80, to improve function. The Discussion distinguishes those ligands from the receptors they engage; this paper does not describe co-expression of additional costimulatory receptors. (LLM, conf=0.88)
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Cites
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- Authors
- Zhao, Z., Condomines, M., van der Stegen, S. J. C., Perna, F., Kloss, C. C., Gunset, G., Plotkin, J., & Sadelain, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Sadelain, Michel
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 28
- Issue
- 4
- Pages
- 415-428
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC5003056
- OpenAlex
- W2144491853
- Cited by
- 843
- References
- 5
- Citations by year
- 2026: 59 · 2025: 76 · 2024: 93 · 2023: 79 · 2022: 90 · 2021: 109 · 2020: 107 · 2019: 77 · 2018: 64 · 2017: 54 · 2016: 29 · 2015: 2
- FWCI
- 21.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Association for Cancer Research
- Cancer Research Institute
- Commonwealth Foundation
- Entertainment Industry Foundation
- Memorial Sloan-Kettering Cancer Center
- Juno Therapeutics
- National Cancer Institute (P30CA008748)
- 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, costimulation, CD28, 4-1BB, CD3, CD19, T cell persistence, T cell exhaustion, adoptive T cell therapy, antitumor immunity
- MeSH terms
- Humans, Interferon-gamma, Kinetics, Lymphocyte Activation, Receptors, Antigen, Recombinant Proteins, T-Lymphocytes, Signal Transduction, Immunotherapy, Adoptive, CD28 Antigens, Antigens, CD19, Hematologic Neoplasms, Interferon Regulatory Factor-7, Tumor Necrosis Factor Receptor Superfamily, Member 9
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