Abstract
One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. Cancer Immunol Res; 6(7); 812-24. ©2018 AACR.
Highlights
Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated success in treating hematologic cancers, such as leukemia and B-cell lymphoma, in preclinical and clinical trials [1,2,3]
Nanoparticles stably attached to the surface of CAR-T cells To improve the efficacy of CAR-engineered T-cell therapy, we used CAR-T cells as chaperones to carry nanoparticles loaded with SCH-58261
Our strategy to enhance CAR T-cell efficacy in solid tumors was to conjugate nanoparticles loaded with a small-molecule inhibitor of the A2a receptor pathway onto the surface of CAR-T cells
Summary
Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has demonstrated success in treating hematologic cancers, such as leukemia and B-cell lymphoma, in preclinical and clinical trials [1,2,3]. This success has not been translated to the treatment of solid tumors [4,5,6]. The TME contains a variety of protumorigenic factors that work to both prevent cancer-killing immune cells from entering the tumor area and dampen the activation of tumor infiltrating lymphocytes Many of these immune suppressive mechanisms can negatively impact adoptively transferred CAR-T cells
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