Abstract
Genetic engineering T cells to create clinically applied chimeric antigen receptor (CAR) T cells has led to improved patient outcomes for some forms of hematopoietic malignancies. While this has inspired the biomedical community to develop similar strategies to treat solid tumor patients, challenges such as the immunosuppressive character of the tumor microenvironment, CAR-T cell persistence and trafficking to the tumor seem to limit CAR-T cell efficacy in solid cancers. This review provides an overview of mechanisms that tumors exploit to evade eradication by CAR-T cells as well as emerging approaches that incorporate genetic engineering technologies to improve CAR-T cell activity against solid tumors.
Highlights
Reconstitution of effective immune function is a major goal of immunotherapies
While this study evaluated samples from only a small number of patients (n = 6), the observation of exhaustion markers on additional immune cells that interact with T cells in order to orchestrate optimal anti-tumor activity may have important implications for control of solid tumors by chimeric antigen receptor (CAR)-T cells
Improved understanding of the complex interactions that occur in the solid tumor microenvironment will lead to improved tailored genetic engineering approaches
Summary
Reconstitution of effective immune function is a major goal of immunotherapies. In the context of cancer, including solid tumors, the complex interaction of various immune cell sub-populations may have to be re-established to obtain adequate tumor control or eradication. Blockade of immunosuppressive TGF-β signaling via expression of a dominant negative TGF-β receptor II in CAR-T cells improved CAR-T cell proliferation, cytokine secretion, in vivo persistence and tumor control in mouse models of human pancreatic cancer [47]. CXCR4 inhibition with AMD3100 treatment led to increased T cell-mediated antitumor activity with concomitant reduction of Tregs, which resulted in improved survival in ovarian cancer and melanoma immunocompetent mouse models [74]. Its deletion resulted in CAR-T cells with improved in vivo persistence and anti-tumor function [87] This is in line with another report that showed molecular refinements to the CAR spacer could impact multiple biological processes in a solid tumor model, including tonic signaling, cell aging, tumor localization, antigen recognition and superior in vivo antitumor activity [88]. Electroporation of Cas9:single guide RNA ribonucleoproteins (Cas9RNP) designed to target CXCR4 resulted in loss of high CXCR4 surface expression in about 40% of cells, and these cells could be further enriched by sorting [104]
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