Improving CAR T-Cell Persistence

Int J Mol Sci. 2021 Oct 7;22(19):10828. doi: 10.3390/ijms221910828.


Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

Keywords: CAR; TRUCK; culturing conditions; exhaustion; lymphodepletion; persistence; stemness.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Immunotherapy, Adoptive / standards*
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Chimeric Antigen / immunology*
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment / immunology*


  • Receptors, Chimeric Antigen