(191by) Adoptive Transfer of CAR-Engineered T Cells with Surface-Conjugated Synthetic Nanoparticles Containing Small Molecule Inhibitors for Reversing Intratumoral T Cell Hypofunction

Adoptive T cell transfers of genetically modified cytotoxic T cells to express chimeric antigen receptors (CAR) have become a promising immunotherapy method. Multiple research studies have shown that adoptive transfer of CAR T cells is successful in patients with B cell hematological malignancies, but is still in the earlier stages of development for treatment of solid tumors. One limiting factor to adoptive T cell therapy is the suppressive tumor microenvironment that inactivates tumor infiltrated T cell (TIL) function. The tumor microenvironment contains high concentration of TIL suppressor molecules such as adenosine that is up taken by the A2A receptor expressed on the cell surface of CD4 and CD8 T cells. Adenosine is generated from extracellular ATP through CD39 and CD73 expressed on the surface of tumor cells and regulatory T cells. We demonstrated that co-delivery of CAR T cells conjugated with crosslinked multilamellar liposomal vesicles (cMLV) encapsulating the A2A receptor inhibitor prevented reduction of CART cell effector function in the tumor microenvironment and effectively restricted tumor growth. We further investigated the application of CART cells as chaperones for drug encapsulating cMLVs to rescue hypofunctional T cells residing in the tumor. In this in vivo study, we showed that the “rescue” system was able to recover TIL function, increase tumor infiltrating CD3+ T cells and decrease the tumor size within 48-h post treatment.