1. Enterotoxins can support CAR T cells against solid tumors.
- Author
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von Scheidt B, Wang M, Oliver AJ, Chan JD, Jana MK, Ali AI, Clow F, Fraser JD, Quinn KM, Darcy PK, Kershaw MH, and Slaney CY
- Subjects
- Animals, Antigen-Presenting Cells drug effects, Antigen-Presenting Cells immunology, CD40 Antigens immunology, Cell Proliferation drug effects, Humans, Immunotherapy, Adoptive, Mice, Mice, Inbred C57BL, Neoplasms genetics, Neoplasms therapy, Receptors, Antigen, T-Cell genetics, T-Lymphocytes cytology, Enterotoxins pharmacology, Neoplasms immunology, Receptors, Antigen, T-Cell immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology
- Abstract
Responses of solid tumors to chimeric antigen receptor (CAR) T cell therapy are often minimal. This is potentially due to a lack of sustained activation and proliferation of CAR T cells when encountering antigen in a profoundly immunosuppressive tumor microenvironment. In this study, we investigate if inducing an interaction between CAR T cells and antigen-presenting cells (APCs) in lymphoid tissue, away from an immunosuppressive microenvironment, could enhance solid-tumor responses. We combined CAR T cell transfer with the bacterial enterotoxin staphylococcal enterotoxin-B (SEB), which naturally links a proportion of T cell receptor (TCR) Vβ subtypes to MHC-II, present on APCs. CAR T cell proliferation and function was significantly enhanced by SEB. Solid tumor-growth inhibition in mice was increased when CAR T cells were administered in combination with SEB. CAR T cell expansion in lymphoid tissue was demonstrated, and inhibition of lymphocyte egress from lymph nodes using FTY720 abrogated the benefit of SEB. We also demonstrate that a bispecific antibody, targeting a c-Myc tag on CAR T cells and cluster of differentiation 40 (CD40), could also enhance CAR T cell activity and mediate increased antitumor activity of CAR T cells. These model systems serve as proof-of-principle that facilitating the interaction of CAR T cells with APCs can enhance their ability to mediate antitumor activity., Competing Interests: The authors declare no competing interest.
- Published
- 2019
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