Sukumaran et al. created “SmarT” CAR T cells that target pancreatic cancer and not normal tissue by requiring independent signaling via three co-occurring events: recognition of a target antigen (prostate stem cell antigen) and presence of two immunosuppressive cytokines (TGFβ and IL4). In vivo, SmarT CAR T cells expanded only in the tumor, eradicated the tumor in a manner that required both CD4+ and CD8+ CARs, contracted shortly after tumor eradication, and persisted for recall response.
The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells has produced tumor responses even in patients with refractory diseases. However, the paucity of antigens that are tumor selective has resulted, on occasion, in "on-target, off-tumor" toxicities. To address this issue, we developed an approach to render T cells responsive to an expression pattern present exclusively at the tumor by using a trio of novel chimeric receptors. Using pancreatic cancer as a model, we demonstrate how T cells engineered with receptors that recognize PSCA, TGFbeta, and IL4, and whose endodomains recapitulate physiologic T cell signaling by providing signals for activation, co-stimulation and cytokine support, produce potent anti-tumor effects selectively at the tumor site. In addition, this strategy has the benefit of rendering our cells resistant to otherwise immunosuppressive cytokines (TGFbeta and IL4) and can be readily extended to other inhibitory molecules present at the tumor site (e.g. PD-L1, IL10, IL13).
Author Info: (1) Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital. (2) Department of Medicine, Center for Cell & Gene Thera
Author Info: (1) Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital. (2) Department of Medicine, Center for Cell & Gene Therapy, Baylor College of Medicine. (3) Center for Cell and Gene Therapy, Baylor College of Medicine. (4) Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital. (5) Surgery, Baylor College of Medicine. (6) Surgery, Baylor College of Medicine. (7) Center for Cell and Gene Therapy, Baylor College of Medicine. (8) Center for Cell and Gene Therapy, Baylor College of Medicine. (9) Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital jfvera@txch.org.
