Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors

Abstract

CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

The next wave of cellular immunotherapies in pancreatic cancer

“… 75 CCL1 has also been shown to assist with homing of CCR8 + T cells toward tumor sites in a murine pancreatic cancer model. 76 The study found that anti-MSLN CAR T cells, engineered to express CCR8, effectively recognized and eliminated target cells where CCR8 + T cells migrated toward the CCL1 gradient.…”

Advances in CAR-T Cell Genetic Engineering Strategies to Overcome Hurdles in Solid Tumors Treatment

“…The team validated this strategy in a murine model of pancreatic cancer and in human xenograft tumor models. Furthermore, this strategy exploits activated T cell derived CCL1 to potentialize a positive feedback loop in CCR8+ cells recruitment to the tumor site ( 64 ).…”

Enhanced Chimeric Antigen Receptor T Cell Therapy through Co-Application of Synergistic Combination Partners

“…Tumor stroma serves as a physical tumor barrier, and the immunosuppressive microenvironment hinders CAR T cells from successfully infiltrating into the tumor site. Regional delivery [ 30 , 31 ] and co-expression of fibroblast activation protein (FAP) [ 32 ], heparanase enzyme [ 33 ], or specific chemokine receptors [ 34 , 35 , 36 , 37 ] on CAR T cells represent potential strategies to improve migration and infiltration. Additional strategies have been developed to shield CAR T cells from inhibitory signals of the tumor microenvironment such as the co-expression of a dominant-negative receptor (DNR) for transforming growth factor beta (TGF-β) [ 37 , 38 , 39 , 40 ].…”

“…Regional delivery [ 30 , 31 ] and co-expression of fibroblast activation protein (FAP) [ 32 ], heparanase enzyme [ 33 ], or specific chemokine receptors [ 34 , 35 , 36 , 37 ] on CAR T cells represent potential strategies to improve migration and infiltration. Additional strategies have been developed to shield CAR T cells from inhibitory signals of the tumor microenvironment such as the co-expression of a dominant-negative receptor (DNR) for transforming growth factor beta (TGF-β) [ 37 , 38 , 39 , 40 ]. Besides these genetic modifications, the combination of other treatment modalities with adoptive T cell therapy may increase the success of this promising therapy [ 41 , 42 , 43 , 44 ].…”