1064 Desmoglein 2 is a Safe and Universal CAR-T Cell Therapy Target in Solid Cancers

Adoptive therapies employing T cells engineered to express a chimeric antigen receptor (CAR) have produced curative outcomes in refractory, progressive hematologic cancers, yet the same potential has yet to be fully realized in epithelial-derived solid tumors. A major obstacle is a limited portfolio of cancer-restricted, cell-surface targets without expression in normal tissues. Desmoglein 2 (DSG2) is a desmosomal cadherin protein universally over-expressed on the surface of transformed cells, with normal protein expression sequestered between cell-to-cell junctions. We hypothesize that this sequestration creates a "window-of-opportunity" to eliminate solid tumor malignancies without off-tumor toxicity. In that context, we generated DSG2-directed CAR-T cells that universally recognize and lyse solid tumor cell lines in vitro. DSG2-directed CAR-T cells eliminated various solid cancer xenografts in vivo, including colon, pancreatic, lung, and squamous cell carcinoma. Tumor re-challenge of previously treated mice indicated persistent in vivo populations of DSG2-directed CAR-T cells capable of rejecting tumors, but not DSG2-deleted (CRISPR/Cas9) tumors. Moreover, syngeneic transfer of species cross-reactive DSG2-directed CAR-T cells produced no overt toxicity targeting murine DSG2, ubiquitously expressed among normal tissues. Likewise, we observed ex vivo recognition and lysis of keratinocytes isolated from mice expressing a human DSG2 transgene when cultured with DSG2-directed CAR-T cells. Human DSG2 transgenic mice receiving DSG2-directed CAR-T cells produced no signs of toxicity, indicating an ability of CAR-T cells to detect DSG2 in an accessible 2D monolayer, but not a sequestered 3D tissue environment. These studies reveal the robust antitumor activity of DSG2-directed CAR-T cells, and introduce a new class of junctionally-restricted antigens that can be safely and effectively targeted across solid tumor types, including skin cancers.