Joining Forces: Improving Clinical Response to Cellular Immunotherapies with Small-Molecule Inhibitors

Trends Mol Med. 2021 Jan;27(1):75-90. doi: 10.1016/j.molmed.2020.09.005. Epub 2020 Sep 30.

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.

Keywords: adaptive resistance; clinical efficacy; combination approach; targeted therapies; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents, Immunological / therapeutic use*
  • Biomarkers, Tumor
  • Cell- and Tissue-Based Therapy* / methods
  • Combined Modality Therapy
  • Humans
  • Immunotherapy* / methods
  • Molecular Targeted Therapy
  • Neoplasms / etiology
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology

Substances

  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor