Joining Forces: Improving Clinical Response to Cellular Immunotherapies with Small-Molecule Inhibitors. Issue 1 (January 2021)

• Record Type: Journal Article
• Authors: Sinha, Debottam; Smith, Corey; Khanna, Rajiv
• Is Part Of: Trends in molecular medicine. Volume 27:Issue 1(2021)
• Page Start: 75
• Page End: 90
• Publication Date: 2021-01
• Subjects: adaptive resistance -- targeted therapies -- combination approach -- clinical efficacy -- tumor microenvironment; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; Physiology, Pathological -- Periodicals; 572.8
• DOI: 10.1016/j.molmed.2020.09.005
• Languages: English
• ISSNs: 1471-4914

Abstract

Abstract : Adoptive T cell therapy (ACT) has emerged as a powerful therapeutic tool against both hematological and virus-associated cancers. However, extension of this success to solid cancers has been challenging owing to intratumoral mechanisms that induce a hostile immunosuppressive tumor microenvironment (TME). Delineating the impact of tumor-intrinsic adaptive resistance mechanisms on immune-based therapies is essential to improve long-term efficacy. We discuss the different tumor-intrinsic factors that lead to resistance to ACT. We highlight the potential of repurposing molecular targeted therapies to modulate immune responses and override intratumor resistance to ACT. Finally, we discuss the potential of combining targeted therapy and ACT as a new paradigm to improve the clinical efficacy of cancer therapeutics. Highlights: ACT has shown excellent efficacy against hematological malignancies. The efficacy of ACT against solid tumors is restricted by multiple tumor-intrinsic molecular mechanisms including the hostile TME. Solid cancer vasculature leads to infiltration of protumor immune cells that impede the trafficking of the effector cytotoxic T cells. Immunosuppressive factors such as checkpoint molecules, cytokines, and toxic metabolic byproducts, as well as hypoxia, limit the therapeutic potential of ACT. Synergistic effects of ACT and immune checkpoint inhibition demonstrate the potential for combination therapies to overcome a hostile TME. Targeted therapies based on small-molecule inhibitors can override inhibitory effects of a hostile TME and improve the clinical response to ACT. Strategies to tackle tumor heterogeneity may improve clinical responses to ACT.