Project 2: Combined CAR-T cell therapy

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PROJECT 2: ABSTRACT Remarkable clinical responses have been reported in B-cell malignancies by adoptive transfer of T cells redirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen. However, developing CAR-Ts for the treatment of solid tumors including pancreatic ductal adenocarcinoma (PDAC) is challenging because: (1) PDAC-associated antigens that are targetable by CAR-Ts are limited, generally not exclusively expressed by PDAC, and act as passengers, not as drivers of tumorigenesis, allowing for antigenic drift; (2) CAR-Ts are defective in their capacity to invade stroma-rich tumors such as PDAC; (3) PDAC tumor microenvironment (TME) is highly immunosuppressive. In this proposal we aim at solving these critical issues. We have identified B7-H3 (CD276) as a suitable target for chimeric antigen receptor (CAR) T cells in PDAC. B7-H3 is a tumor- promoting transmembrane protein aberrantly expressed in 60% to 93% of PDAC, melanoma, leukemia, breast, prostate and ovarian cancer, while limited expression is seen on normal healthy tissues. We have developed and tested B7-H3.CAR-Ts in xenogeneic and immunocompetent mouse models of PDAC showing antitumor activity and safety. Thus in Aim 1 we propose to develop a phase I clinical study in patients with PDAC to assess safety and antitumor activity of B7-H3.CAR-Ts that also include the inducible caspase9 (iC9) as a safety switch to terminate the activity of B7-H3.CAR-Ts in case of toxicity. In Aim 2 we propose to develop in preclinical models CAR-Ts in which T cells are not be only rendered tumor specific through the CAR expression, but are also equipped to overcome the desmoplastic nature of PDAC. Specifically, B7-H3.CAR-Ts will be further engineered to re-express the enzyme heparanase (HPSE), which is defective in CAR-Ts generated for clinical use. Furthermore, we will explore if the glucose-regulated protein of 94 kDa (gp96 or Grp94), which is a member of the heat shock protein (HSP) 90 family (HSP90B1) can also be used as additional target in PDAC to prevent tumor escape due to antigen loss when one single antigen is targeted. In Aim 3 we propose to reprogram macrophages and myeloid derived suppressor cells (MDSC) to a non- immunosuppressive state by using potent and orally bioavailable TAM RTK small molecule inhibitors developed at University of North Carolina (IND #128236). We will thus perform preclinical studies to evaluate whether TAM RTK signaling inhibition in macrophages and MDSC would favor the antitumor activity of B7- H3.CAR-Ts. If successful, this strategy will be included into a second phase of the proposed Phase I clinical study with B7-H3.CAR-Ts.