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Cited by 207CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

CAR-T cell performance: How to improve their persistence?

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López-Cantillo, Gina, Urueña, Claudia, Camacho, Bernardo Armando, Ramírez-Segura, Cesar·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.878209PMC PMC9097681
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Abstract

Adoptive cell therapy with T cells reprogrammed to express chimeric antigen receptors (CAR-T cells) has been highly successful in patients with hematological neoplasms. However, its therapeutic benefits have been limited in solid tumor cases. Even those patients who respond to this immunotherapy remain at risk of relapse due to the short-term persistence or non-expansion of CAR-T cells; moreover, the hostile tumor microenvironment (TME) leads to the dysfunction of these cells after reinfusion. Some research has shown that, in adoptive T-cell therapies, the presence of less differentiated T-cell subsets within the infusion product is associated with better clinical outcomes. Naive and memory T cells persist longer and exhibit greater antitumor activity than effector T cells. Therefore, new methods are being studied to overcome the limitations of this therapy to generate CAR-T cells with these ideal phenotypes. In this paper, we review the characteristics of T-cell subsets and their implications in the clinical outcomes of adoptive therapy with CAR-T cells. In addition, we describe some strategies developed to overcome the reduced persistence of CAR T-cells and alternatives to improve this therapy by increasing the expansion ability and longevity of modified T cells. These methods include cell culture optimization, incorporating homeostatic cytokines during the expansion phase of manufacturing, modulation of CAR-T cell metabolism, manipulating signaling pathways involved in T-cell differentiation, and strategies related to CAR construct designs.

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  • More mature T cell subtypes generally exert greater effector function in vivo.

    “Additionally, we demonstrated for the first time that circulating CAR-T cells at its peak persistence were mostly TCM and TEM, thus confirming that CAR-T cells differentiated into more mature subtypes, which generally exert greater effector function in vivo.33,34”

    From Point-of-care manufacturing of anti-CD19 CAR-T cells using a closed production platform: Experiences of an academic in Thailand (2024) · cites this paper as [33]

    The Effector Memory T Cells and Terminal Effector T Cells sections describe more differentiated subsets as more cytotoxic or capable of potent, rapid effector responses. But the CAR-T Cell Differentiation Stage and Treatment Response section reports greater antitumor potency and persistence for CAR-T cells derived from less differentiated subsets than from effector memory cells. The source therefore supports greater immediate effector capacity for some mature subsets, not the generalization that they exert greater effector function in vivo. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

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References 170 · Cited by 207

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Authors
López-Cantillo, G., Urueña, C., Camacho, B. A., & Ramírez-Segura, C.
Affiliations
Pontificia Universidad Javeriana (CO)
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-04-28
Volume
13
Pages
878209-878209
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.878209
PMC
PMC9097681
OpenAlex
W4285742411
Cited by
207
References
170
Citations by year
2026: 53 · 2025: 63 · 2024: 59 · 2023: 26 · 2022: 6
FWCI
4.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
chimeric antigen receptor T cells, T cell persistence, T cell subsets, naive T cells, memory T cells, effector T cells, tumor microenvironment, solid tumors, relapse, T cell differentiation, homeostatic cytokines, T cell metabolism, automotive design, cell expansion, adoptive T cell therapy
MeSH terms
Receptors, Chimeric Antigen, Humans, Lymphocyte Activation, Neoplasm Recurrence, Local, Immunotherapy, Adoptive, Tumor Microenvironment

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