Project 4: Activity of CAR T cell Therapy for Patients with Metastatic TNBC

PROJECT 4: Activity of Car T Cell Therapy for Patients With Metastatic TNBC - Abstract Triple negative breast cancer (TNBC) remains a tumor with dismal prognosis even in the era of immune checkpoint inhibitors (ICIs). Here we propose to develop chimeric antigen receptor T cells (CAR-Ts) to target TNBC. Specifically, we will target the B7-H3 antigen that is aberrantly expressed in several solid tumors including TNBC, but has limited expression in normal tissues. In Aim 1, we will conduct a Phase I clinical study infusing autologous B7-H3.CAR-Ts in patients with TNBC. Solid tumors including TNBC are characterized by heterogeneity of antigen expression and can escape immune targeting directed against a single antigen. Furthermore, brain metastases of TNBC remain difficult to treat due to the presence of the blood-brain-barrier (BBB) that poses physical impediment to both drugs and immune cells. In Aim 2 we propose to develop preclinical models of TNBC to test dual CAR-Ts targeting B7-H3 and chondroitin sulphate proteoglycan 4 (CSPG4) using a novel dual CAR design and to engineer dual CAR-Ts to express the CCR2b chemokine receptor, which we found to promote CAR-T cell trafficking through the BBB when brain metastases produces the CCL2 chemokine. The inhibitory TME contributes to attenuating CAR-T cell functions. We implemented a model of CAR-Ts in immunocompetent mice and demonstrated that Th/Tc17 polarized CAR-Ts combined with STING agonists prompted superior tumor control compared to conventional CAR-Ts. Furthermore, STING agonist 2'3' cGAMP leads to significant enrichment of T cells with stem cell (TSCM) and central-memory (TCM) characteristics both in vitro and in vivo. In Aim 3, we will assess the mechanism and antitumor activity of Th/Tc17 CAR-Ts activated by cGAMP in modulating the breast cancer TME and enhancing the expansion of CAR-Ts in the TME.