Use of Ly6K specific CAR T-cells to treat primary and metastatic triple negative breast cancer

Project Summary/abstract We have identified that increased Ly6K expression is associated with poor outcome in triple negative breast cancer (TNBC). Mechanistically, Ly6K is required for the activation of TGFβ signaling and is increased in tumorigenesis in vivo. We propose that the biomarker Ly6K is an ideal therapeutic target for the treatment of TNBC because this protein is not expressed in normal cells, except in testis. Ly6K is also not required for vital organ function, except for spermatogenesis. Thus, targeting this protein for the treatment of TNBC, a disease affecting mostly females, is appropriate and ideal. Because of this, Ly6K is an optimal therapeutic target for TNBC immunotherapy using CAR T-cells. CAR T-cells are genetically modified T cells which express a chimeric antigen receptor fusion protein (CAR) derived from a monoclonal antibody (mAb) recognizing a target protein on the surface of cancer cells. CAR T-cells can recognize and kill target cells expressing the target protein without the need for HLA matching. We have generated three high affinity mAbs against human Ly6K, which recognize the cell surface Ly6K on cancer cells. The sequences from Ly6K mAbs were used to generate a CAR in a third generation lentiviral CAR vector to generate Ly6K-specific CAR T-cells. We will test whether Ly6K-specific CAR T-cells will recognize cancer cells expressing cell surface Ly6K and eliminate them in primary and metastatic TNBC mouse models.