1. Enterotoxins can support CAR T cells against solid tumors.
- Author
-
von Scheidt, Bianca, Minyu Wang, Oliver, Amanda J., Chan, Jack D., Jana, Metta K., Ali, Aesha I., Clow, Fiona, Fraser, John D., Quinn, Kylie M., Darcy, Phillip K., Kershaw, Michael H., and Slaney, Clare Y.
- Subjects
T cells ,T cell differentiation ,ENTEROTOXINS ,T cell receptors ,BISPECIFIC antibodies - 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 increasedwhen CAR T cellswere 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. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF