Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15
Abstract
The genetic transfer of antigen receptors provides a means to rapidly generate autologous tumor-reactive T lymphocytes. However, recognition of tumor antigens by cytotoxic T cells is only one step towards effective cancer immunotherapy. Other crucial biological prerequisites must be fulfilled to expand tumor-reactive T cells that retain a functional phenotype, including in vivo cytolytic activity and the ability to travel to tumor sites without prematurely succumbing to apoptosis. We show that these requirements are met by expanding peripheral blood T cells genetically targeted to the CD19 antigen in the presence of CD80 and interleukin-15 (IL-15). T cells expanded in the presence of IL-15 uniquely persist in tumor-bearing severe combined immunodeficiency (SCID)-Beige mice and eradicate disseminated intramedullary tumors. Their anti-tumor activity is further enhanced by in vivo co-stimulation. In addition, transduced T cells from patients with chronic lymphocytic leukemia (CLL) effectively lyse autologous tumor cells. These findings strongly support the clinical feasibility of this therapeutic strategy.
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Most clinical protocols and all commercially approved therapies have relied on viral vectors to deliver CAR transgenes into T cells.
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- Authors
- Brentjens, R. J., Latouche, J.-B., Santos, E., Marti, F., Gong, M. C., Lyddane, C., King, P. D., Larson, S., Weiss, M., Rivière, I., & Sadelain, M.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Hospital for Special Surgery (US)
- Corresponding author
- Sadelain, Michel
- ORCID
- Venue
- Nature Medicine
- Published
- 2003-02-10
- Volume
- 9
- Issue
- 3
- Pages
- 279-286
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W1983056774
- Cited by
- 669
- References
- 0
- Citations by year
- 2026: 17 · 2025: 29 · 2024: 39 · 2023: 38 · 2022: 23 · 2021: 44 · 2020: 33 · 2019: 32 · 2018: 39 · 2017: 33 · 2016: 27 · 2015: 36 · 2014: 21 · 2013: 26 · 2012: 16
- FWCI
- 11.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 86438, CA08748, CA83084, P50CA086438, CA-59350, P01CA059350, P30CA008748)
- National Institute of Allergy and Infectious Diseases (AI44926, R01AI044926)
- 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
- adoptive T cell therapy, genetically modified T cells, CD19, IL-15, B-cell malignancies, chronic lymphocytic leukemia, cancer immunotherapy, T cell persistence, SCID-hu mice, T cell expansion
- MeSH terms
- Animals, B-Lymphocytes, Bone Marrow, Humans, Lymphocyte Activation, Neoplasms, Recombinant Fusion Proteins, T-Lymphocytes, Tomography, Emission-Computed, Tumor Cells, Cultured, Biomarkers, Tumor, Survival Rate, Immunotherapy, Adoptive, Mice, SCID, B7-1 Antigen, Antigens, CD19, Adoptive Transfer, Interleukin-15, Mice
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