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Synthetic cytokine circuits that drive T cells into immune-excluded tumors.

Greg M AllenNicholas W FrankelNishith R ReddyHersh K BhargavaMaia A YoshidaSierra R StarkMegan PurlJungmin LeeJacqueline L YeeWei YuAileen W LiK Christopher GarciaHana El-SamadKole T RoybalMatthew H SpitzerWendell A Lim
Published in: Science (New York, N.Y.) (2022)
Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.
Keyphrases
  • induced apoptosis
  • oxidative stress
  • cell therapy
  • cell cycle arrest
  • diabetic rats
  • drug induced
  • endothelial cells
  • dendritic cells
  • bone marrow
  • signaling pathway
  • pi k akt