Prolonged Persistence of Chimeric Antigen Receptor (CAR) T Cell in Adoptive Cancer Immunotherapy: Challenges and Ways Forward

Abstract

CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments. CAR T cell qualities, such as persistence and functionality play important roles in determining the outcome of cancer immunotherapy. In spite of full functionality, it has been shown that poor persistence of CAR T cells can limit an effective antitumor immune response. Here, we outline specific strategies that can be employed to overcome intrinsic and extrinsic barriers to CAR T cell persistence. We also offer our viewpoint on how growing use of CAR T cells in various cancers may require modifications in the intrinsic and extrinsic survival signals of CAR T cells. We anticipate these amendments will additionally provide the rationales for generation of more persistent, and thereby, more effective CAR T cell treatments.

Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer

“…1,2 CAR T cell therapy represent a true "vital drug" that has immediate and specific effects against cancer cells, and that may potentially provide long-term protection due to the persistence of immune memory cells. 3,4 CARs are constructed by fusing an extracellular antigen-binding portion, commonly the single-chain variable fragment (scFv) of a tumour-reactive monoclonal antibody (mAb), with intracellular activation units, usually the CD3ζ-chain, coupled with costimulatory endodomains from either CD28 or 41BB. 5 The expression of CAR molecules in T lymphocytes is usually obtained by transduction with viral vectors.…”

ERBB2-CAR-Engineered Cytokine-Induced Killer Cells Exhibit Both CAR-Mediated and Innate Immunity Against High-Risk Rhabdomyosarcoma

“…It is widely recognized that CAR-engineered T cell products lose in vivo function during culture, driving the development of ever-shorter manufacturing protocols (43)(44)(45). In previous work, we employed CIK cells after ex vivo activation with IL-15 for 10 days, which resulted in more rapid generation of CIK cells with stronger cytotoxicity compared to conventional CIK cells expanded in the absence of IL-15 over 3-4 weeks.…”

Adoptive Cell Therapy in Hepatocellular Carcinoma: Biological Rationale and First Results in Early Phase Clinical Trials

“…Technical solutions to enhance persistence were extensively reviewed elsewhere [ 116 ] and notably include: (i) the improvement of intracellular co-stimulation (e.g., CD28); (ii) the manipulation of T cells to express cytokines and their receptors (IL15–IL21: GPC3-CAR-T cells) [ 117 ]; (iii) the combination with PD(L)1 inhibitors; (iv) the modification of conditioning regimen (for example the use of conditioning with 5-Azacytidine or Fludarabine) [ 118 ].…”