期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 48, 页码 E7788-E7797出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1610544113
关键词
adoptive immunotherapy; CAR; IL-15; T-memory stem cell; T-cell persistence
资金
- Andrew Sowell-Wade Huggins Scholarship in Cancer Research (Cancer Answers Foundation)
- Center for Clinical and Translational Sciences T32 Grant Trainee support (NIH)
- Center for Clinical and Translational Sciences
- National Center for Advancing Translational Sciences of the NIH [TL1TR000369]
- Cancer Center Core Grant [CA16672]
- Research Project Grants R01 [CA124782, CA120956, CA141303]
- Research Program Project P01 [CA148600]
- Specialized Programs of Research Excellence [CA100632, CA136411, CA00632]
- Albert J. Ward Foundation
- Alex's Lemonade Stand Foundation
- Burroughs Wellcome Fund
- Cancer Prevention and Research Institute of Texas
- Charles B. Goddard Foundation of Texas
- CLL Global Research Foundation
- Energy Transfer Partners
- Estate of Noelan L. Bibler
- Gillson Longenbaugh Foundation
- Harry T. Mangurian, Jr., Fund for Leukemia Immunotherapy
- Khalifa Bin Zayed Al Nahyan Foundation
- Kleberg Foundation
- Leukemia and Lymphoma Society
- Lymphoma Research Foundation
- Miller Foundation
- National Foundation for Cancer Research
- Pediatric Cancer Research Foundation
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy
- University of Texas M. D. Anderson Cancer Center Sister Institution Network Fund
- Moon Shot Fund
- William Lawrence and Blanche Hughes Children's Foundation
Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (T-SCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved T-SCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19(+) leukemia. Long-lived T cells were CD45RO(neg)CCR7(+) CD95(+), phenotypically most similar to T-SCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR(+) T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.
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