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Enterotoxins can support CAR T cells against solid tumors.

Bianca von ScheidtMinyu WangAmanda J OliverJack D ChanMetta K JanaAesha I AliFiona ClowJohn D FraserKylie M QuinnPhillip K DarcyMichael H KershawClare Y Slaney
Published in: Proceedings of the National Academy of Sciences of the United States of America (2019)
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.
Keyphrases
  • cell therapy
  • cell proliferation
  • stem cells
  • lymph node
  • cell death
  • skeletal muscle
  • dendritic cells
  • case report
  • binding protein
  • peripheral blood
  • pi k akt
  • methicillin resistant staphylococcus aureus
  • locally advanced