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Cited by 134CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Next-generation manufacturing protocols enriching TSCM CAR T cells can overcome disease-specific T cell defects in cancer patients

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Arcangeli, Silvia, Falcone, Laura, Camisa, Barbara, De Girardi, Federica, Biondi, Marta, Giglio, Fabio, Ciceri, Fabio, Bonini, Chiara +2 more·2020·Frontiers in Immunology
DOI 10.3389/fimmu.2020.01217PMC PMC7317024
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Abstract

Chimeric antigen receptor (CAR) T cell expansion and persistence emerged as key efficacy determinants in cancer patients. These features are typical of early-memory T cells, which can be enriched with specific manufacturing procedures, providing signal one and signal two in the proper steric conformation and in the presence of homeostatic cytokines. In this project, we exploited our expertise with paramagnetic beads and IL-7/IL-15 to develop an optimized protocol for CAR T cell production based on reagents, including a polymeric nanomatrix, which are compatible with automated manufacturing via the CliniMACS Prodigy. We found that both procedures generate similar CAR T cell products, highly enriched of stem cell memory T cells (TSCM) and equally effective in counteracting tumor growth in xenograft mouse models. Most importantly, the optimized protocol was able to expand CAR TSCM from B-cell acute lymphoblastic leukemia (B-ALL) patients, which in origin were highly enriched of late-memory and exhausted T cells. Notably, CAR T cells derived from B-ALL patients proved to be as efficient as healthy donor-derived CAR T cells in mediating profound and prolonged anti-tumor responses in xenograft mouse models. On the contrary, the protocol failed to expand fully functional CAR TSCM from patients with pancreatic ductal adenocarcinoma, suggesting that patient-specific factors may profoundly affect intrinsic T-cell quality. Finally, by retrospective analysis of in vivo data, we observed that the proportion of TSCM in the final CAR T cell product positively correlated with in vivo expansion, which in turn proved to be crucial for achieving long-term remissions. Collectively, our data indicate that next-generation manufacturing protocols can overcome initial T-cell defects, resulting in TSCM-enriched CAR T cell products qualitatively equivalent to the ones generated from healthy donors. However, this positive effect may be decreased in specific conditions, for which the development of further improved protocols and novel strategies might be highly beneficial.

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  • Early memory T cell subsets (naive, stem cell memory, and central memory T cells) are long-lived, possess high self-renewal ability, and exhibit long-term persistence and superior antitumor response in vivo.

    “It is widely accepted that early memory T cell subsets (e.g., naive [TN], stem cell memory [TSCM] and central memory [TCM]T cells), which are long-lived and possess high self-renewal ability, exhibit long-term persistence and superior antitumor response in vivo.17,18,19”

    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 [17]

    The Introduction (page unavailable) says that enriching TSCM and TCM CAR T cells can enhance persistence and support a long-lasting antitumor response; the Results also link TSCM frequency to expansion in vivo. The paper does not establish that all three listed subsets, including naive T cells, are long-lived and highly self-renewing, or that each exhibits superior antitumor responses in vivo. (LLM, conf=0.85)

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References 52 · Cited by 134

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Authors
Arcangeli, S., Falcone, L., Camisa, B., De Girardi, F., Biondi, M., Giglio, F., Ciceri, F., Bonini, C., Bondanza, A., & Casucci, M.
Affiliations
  • IRCCS Ospedale San Raffaele (IT)
  • Vita-Salute San Raffaele University (IT)
Corresponding author
Casucci, Monica
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2020-06-19
Volume
11
Pages
1217-1217
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2020.01217
PMC
PMC7317024
OpenAlex
W3036078444
Cited by
134
References
52
Citations by year
2026: 16 · 2025: 26 · 2024: 29 · 2023: 21 · 2022: 20 · 2021: 18 · 2020: 4
FWCI
5.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
Funders
European Commission (HORIZON2020)
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, stem cell memory T cells, CAR T cell manufacturing, B-cell acute lymphoblastic leukemia, pancreatic ductal adenocarcinoma, T cell exhaustion, xenograft mouse model
MeSH terms
Receptors, Chimeric Antigen, Animals, Humans, Neoplasms, T-Lymphocytes, Technology, Pharmaceutical, Immunotherapy, Adoptive, Immunomagnetic Separation, Xenograft Model Antitumor Assays, Mice

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