CAR T Cell Immunotherapy Beyond Haematological Malignancy

Abstract

Chimeric antigen receptor (CAR) T cells, which express a synthetic receptor engineered to target specific antigens, have demonstrated remarkable potential to treat haematological malignancies. However, their transition beyond haematological malignancy has so far been unsatisfactory. Here, we discuss recent challenges and improvements for CAR T cell therapy against solid tumors: Antigen heterogeneity which provides an effective escape mechanism against conventional mono-antigen-specific CAR T cells; and the immunosuppressive tumor microenvironment which provides physical and molecular barriers that respectively prevent T cell infiltration and drive T cell dysfunction and hypoproliferation. Further, we discuss the application of CAR T cells in infectious disease and autoimmunity.

Drug Delivery Opportunities in Esophageal Cancer: Current Treatments and Future Prospects

“…Recent clinical successes in melanoma, 264 sarcoma, 265 and colorectal carcinoma 266 are prompting clinical investigation for the treatment of esophageal cancer. 267,268 Given the significant research in melanoma, lung, breast, ovarian, and bladder cancers, antigens are known which are upregulated in epithelial carcinomas but with limited expression in healthy normal adult tissue. 269−274 Far fewer upregulated antigens are known for esophageal cancer, with candidates including MUC1, HER2, EpCAM, CLDN18.2, MAGE-A3, MAGE-A4, and NY-ESO-1.…”

“…Clinically, T cells are harvested from the patient, engineered to target a specific antigen on the cancer cell surface, and then introduced into the patient’s immune system. Recent clinical successes in melanoma, sarcoma, and colorectal carcinoma are prompting clinical investigation for the treatment of esophageal cancer. , Given the significant research in melanoma, lung, breast, ovarian, and bladder cancers, antigens are known which are upregulated in epithelial carcinomas but with limited expression in healthy normal adult tissue. − Far fewer upregulated antigens are known for esophageal cancer, with candidates including MUC1, HER2, EpCAM, CLDN18.2, MAGE-A3, MAGE-A4, and NY-ESO-1. − Success targeting these antigens with CAR-T and TCR-T therapies both in vitro, in vivo, and in clinical trials provides motivation for further studies. ,− Lu et al report a partial response with treatment using autologous MAGE A3 engineered T cells with only minimal adverse reactions. In contrast, Morgan et al note that some patients suffered from neurological toxicities .…”

Mechanisms of immune modulation in the tumor microenvironment and implications for targeted therapy

“…Next-generation bi-specific CAR-Ts are being developed to overcome these challenges ( 95 ), these include fourth and fifth generation CAR-Ts delivering drugs able to modify the TME through the release of transgenic immune modulators ( 96 ). Chimeric antigen receptor macrophage-cells ( CAR-M) can destroy tumor cells or alter the TME creating a niche of tumor and immune cells.…”

CAR-NK cell therapy for glioblastoma: what to do next?

“…The activated T cells in vitro are modified by the chimeric antigen receptor gene to form CAR-T cells. CAR-T cells target tumor-associated antigens through their expressed chimeric antigen receptors, specifically recognizing and killing tumor cells ( 9 ) ( 10 ). Due to the excellent anti-tumor effect of CAR-T cells, the United States first approved two CAR-T drugs for treating non-Hodgkin’s lymphoma and acute lymphoblastic leukemia in 2017.…”