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Cited by 312CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Reducing Ex Vivo Culture Improves the Antileukemic Activity of Chimeric Antigen Receptor (CAR) T Cells

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Ghassemi, Saba, Nunez-Cruz, Selene, O'Connor, Roddy S., Fraietta, Joseph A., Patel, Prachi R., Scholler, John, Barrett, David M., Lundh, Stefan M. +10 more·2018·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-17-0405PMC PMC8274631

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Abstract

The success of chimeric antigen receptor (CAR)–mediated immunotherapy in acute lymphoblastic leukemia (ALL) highlights the potential of T-cell therapies with directed cytotoxicity against specific tumor antigens. The efficacy of CAR T-cell therapy depends on the engraftment and persistence of T cells following adoptive transfer. Most protocols for T-cell engineering routinely expand T cells ex vivo for 9 to 14 days. Because the potential for engraftment and persistence is related to the state of T-cell differentiation, we hypothesized that reducing the duration of ex vivo culture would limit differentiation and enhance the efficacy of CAR T-cell therapy. We demonstrated that T cells with a CAR-targeting CD19 (CART19) exhibited less differentiation and enhanced effector function in vitro when harvested from cultures at earlier (day 3 or 5) compared with later (day 9) timepoints. We then compared the therapeutic potential of early versus late harvested CART19 in a murine xenograft model of ALL and showed that the antileukemic activity inversely correlated with ex vivo culture time: day 3 harvested cells showed robust tumor control despite using a 6-fold lower dose of CART19, whereas day 9 cells failed to control leukemia at limited cell doses. We also demonstrated the feasibility of an abbreviated culture in a large-scale current good manufacturing practice–compliant process. Limiting the interval between T-cell isolation and CAR treatment is critical for patients with rapidly progressing disease. Generating CAR T cells in less time also improves potency, which is central to the effectiveness of these therapies. Cancer Immunol Res; 6(9); 1100–9. ©2018 AACR.

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  • A phase I clinical trial investigating this novel therapeutic approach in 18 subjects with locally advanced (unresectable) or metastatic HER2+ solid tumors has commenced.

    “A phase I clinical trial to investigate this novel therapeutic approach in 18 subjects with locally advanced (unresectable) or metastatic HER2+ solid tumors has commenced (NCT04660929) (121).”

    From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [121]

    The Materials and Methods section (‘Cells and cell cultures’; page unavailable) lists different clinical-trial identifiers and describes samples from patients with leukemia and ovarian cancer. A HER2-specific phase I glioblastoma trial appears only in the References (page unavailable). Searches for NCT04660929 and a trial of 18 subjects with locally advanced or metastatic HER2-positive solid tumors found no passage addressing the claimed trial. (LLM, conf=0.76)

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Authors
Ghassemi, S., Nunez-Cruz, S., O'Connor, R. S., Fraietta, J. A., Patel, P. R., Scholler, J., Barrett, D. M., Lundh, S. M., Davis, M. M., Bedoya, F., Zhang, C., Leferovich, J., Lacey, S. F., Levine, B. L., Grupp, S. A., June, C. H., Melenhorst, J. J., & Milone, M. C.
Affiliations
  • University of Pennsylvania (US)
  • 1Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Children's Hospital of Philadelphia (US)
Corresponding author
  • Ghassemi, Saba
  • Milone, Michael C.
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2018-09-01
Volume
6
Issue
9
Pages
1100-1109
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-17-0405
PMC
PMC8274631
OpenAlex
W2884835745
Cited by
312
References
3
Citations by year
2026: 40 · 2025: 48 · 2024: 46 · 2023: 46 · 2022: 30 · 2021: 29 · 2020: 39 · 2019: 29 · 2018: 5
FWCI
9.58
Type
journal article
Language
en
Open access
Locations
  • Cancer Immunology Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
Novartis (N/A)
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, CAR T-cell therapy, acute lymphoblastic leukemia, CD19, T cell differentiation, antileukemic activity, murine xenograft model, adoptive cell transfer
MeSH terms
Receptors, Chimeric Antigen, Animals, Antigens, Neoplasm, Cell Differentiation, Cytotoxicity, Immunologic, Humans, Lymphocyte Activation, T-Lymphocytes, Time Factors, Immunotherapy, Adoptive, Cell Culture Techniques, Antigens, CD19, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma

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