Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies
Abstract
Engineered T cell therapies have begun to demonstrate impressive clinical responses in patients with B cell malignancies. Despite this efficacy, many patients are unable to receive T cell therapy because of failure of in vitro expansion, a necessary component of cell manufacture and a predictor of in vivo activity. To evaluate the biology underlying these functional differences, we investigated T cell expansion potential and memory phenotype during chemotherapy in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). We found that patients with T cell populations enriched for early lineage cells expanded better in vitro and that patients with ALL had higher numbers of these cells with a corresponding enhancement in expansion as compared to cells from patients with NHL. We further demonstrated that early lineage cells were selectively depleted by cyclophosphamide and cytarabine chemotherapy and that culture with interleukin-7 (IL-7) and IL-15 enriched select early lineage cells and rescued T cell expansion capability. Thus, early lineage cells are essential to T cell fitness for expansion, and enrichment of this population either by timing of T cell collection or culture method can increase the number of patients eligible to receive highly active engineered cellular therapies.
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The composition of autologous starting material from cancer patients is highly variable, influenced by patient age and defects due to underlying disease or pre-treatment with lymphotoxic agents.
“However, the composition of autologous starting material from cancer patients is highly variable, influenced by patient age and defects due to underlying disease or pre-treatment with lymphotoxic agents (35-38).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [35]
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“For instance, memory T cell concentrations in patients with ALL and non-Hodgkin lymphoma (NHL) decrease with each course of standard-of-care treatment (35).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [35]
Depletion of memory T cells could result in failure of manufacture or functionality of CAR T cells.
“This depletion could result in failure of manufacture or functionality of CAR T cells (35).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [35]
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- Authors
- Singh, N., Perazzelli, J., Grupp, S. A., & Barrett, D. M.
- Affiliations
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Corresponding author
- Singh, Nathan
- Venue
- Science Translational Medicine
- Published
- 2016-01-06
- Volume
- 8
- Issue
- 320
- Pages
- 320ra3-320ra3
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2228689854
- Cited by
- 303
- References
- 5
- Citations by year
- 2026: 21 · 2025: 18 · 2024: 36 · 2023: 31 · 2022: 36 · 2021: 34 · 2020: 36 · 2019: 32 · 2018: 28 · 2017: 17 · 2016: 13 · 2012: 1
- FWCI
- 16.09
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leukemia and Lymphoma Society
- Weinberg Funds
- Cookies for Kids' Cancer
- Stand Up To Cancer_St. Baldrick's Pediatric Dream Team Translational Research (SU2C-AACR-DT1113)
- Pennsylvania Department of Health
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Keywords
- T cell expansion, memory T cells, pediatric malignancies, acute lymphoblastic leukemia, non-Hodgkin lymphoma, chemotherapy, cyclophosphamide, cytarabine, IL-7, IL-15, T cell therapy, engineered T cell therapy, T cell fitness
- MeSH terms
- Adolescent, Child, Child, Preschool, Female, Humans, Immunologic Memory, Infant, Male, Neoplasms, Phenotype, T-Lymphocytes, Interleukin-7, Cell Lineage, Interleukin-15, Cell Proliferation
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