1144 Combined CAR-M and T cell therapy to remodel TGFbeta-rich solid tumors

Background

We propose combining CAR-M and T cell therapy to maximize therapeutic effect by leveraging tumor infiltration and antigen presentation. Through in silico analysis of TME, we identified TGFb as a major culprit of T cell suppression. We hypothesize that letting CAR-M secreting anti-TGFb scFv could reprogram immunosuppressive TME.

Methods

We engineered CAR-M to secrete anti-TGFb scFv (AB-CAR-M) and examined its interaction with T cell and tumor in vitro and in vivo.

Results

We validated its blocking effect in the SMAD-reporter cell system. More importantly, we reinvigorated T cells and macrophages through TGFb blocking. Supernatant from AB-CAR-M induced cytotoxic T cell program, suppressed Treg program, and enhanced CD80+ inflammatory macrophages via canceling TGFb. Our key observation is that AB-CAR-M enhanced T cell killing of cancer. We use both NSG tumor-bearing mice administered with human AB-CAR-M + T cells and immunocompetent liver cancer mice administered with murine AB-CAR-M. With scRNA-seq, Stereo-Seq, and TCR-seq, we are identifying the spatial organization of AB-CAR-M, T cells, and cancer.

Conclusions

Our ultimate goal is to identify unique clonally expanded TCR for gene therapy or its neoepitope for cancer vaccine. We expect these therapies will synergize with adaptive cell therapy.