CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
Open accessAbstract
BACKGROUND: T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells. METHODS: We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy. RESULTS: The defined composition product was remarkably potent, as 27 of 29 patients (93%) achieved BM remission, as determined by flow cytometry. We established that high CAR-T cell doses and tumor burden increase the risks of severe cytokine release syndrome and neurotoxicity. Moreover, we identified serum biomarkers that allow testing of early intervention strategies in patients at the highest risk of toxicity. Risk-stratified CAR-T cell dosing based on BM disease burden decreased toxicity. CD8+ T cell-mediated anti-CAR transgene product immune responses developed after CAR-T cell infusion in some patients, limited CAR-T cell persistence, and increased relapse risk. Addition of fludarabine to the lymphodepletion regimen improved CAR-T cell persistence and disease-free survival. CONCLUSION: Immunotherapy with a CAR-T cell product of defined composition enabled identification of factors that correlated with CAR-T cell expansion, persistence, and toxicity and facilitated design of lymphodepletion and CAR-T cell dosing strategies that mitigated toxicity and improved disease-free survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT01865617. FUNDING: R01-CA136551; Life Science Development Fund; Juno Therapeutics; Bezos Family Foundation.
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Clinical trials using CD19-targeted CAR T-cell therapy for B-cell acute lymphoblastic leukemia have demonstrated high efficacy, with durable complete response rates in >60% of patients with relapsed or refractory disease.
“Clinical trials using CD19-targeted CAR T-cell therapy for B-cell acute lymphoblastic leukemia have demonstrated high efficacy, with durable complete response rates in >60% of patients with relapsed or refractory disease [74, 75].”
From Clinical use of lentiviral vectors (2018) · cites this paper as [75]
The Clinical response section reports bone-marrow remission in 27 of 29 evaluable patients (93%), supporting high initial efficacy in relapsed or refractory B-ALL. But the paper does not establish a durable complete-response rate above 60% for the trial overall: the section on adding fludarabine reports seven subsequent relapses in the earlier treatment group and describes follow-up in the fludarabine group as short. (LLM, conf=0.86)
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- Authors
- Turtle, C. J., Hanafi, L.-A., Berger, C., Gooley, T. A., Cherian, S., Hudecek, M., Sommermeyer, D., Melville, K., Pender, B., Budiarto, T. M., Robinson, E., Steevens, N. N., Chaney, C., Soma, L., Chen, X., Yeung, C., Wood, B., Li, D., Cao, J., Heimfeld, S., Jensen, M. C., Riddell, S. R., & Maloney, D. G.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Juno Therapeutics (United States) (US)
- Corresponding author
- Turtle, Cameron J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-04-25
- Volume
- 126
- Issue
- 6
- Pages
- 2123-2138
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4887159
- OpenAlex
- W2342423058
- Cited by
- 2,112
- References
- 30
- Citations by year
- 2026: 112 · 2025: 150 · 2024: 204 · 2023: 221 · 2022: 249 · 2021: 248 · 2020: 286 · 2019: 224 · 2018: 206 · 2017: 166 · 2016: 41 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 114.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Damon Runyon Cancer Research Foundation
- Gilead Sciences
- Fred Hutchinson Cancer Research Center
- Juno Therapeutics
- National Cancer Institute (CA136551, R01CA136551, P30CA015704)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK106829)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD19 CAR T cells, B-cell acute lymphoblastic leukemia, CD4+ T cells, CD8+ T cells, lymphodepletion chemotherapy, fludarabine, cytokine release syndrome, neurotoxicity, serum biomarkers, CAR T cell persistence, relapse risk, disease-free survival
- MeSH terms
- Adult, Aged, Humans, Lymphocyte Depletion, Middle Aged, Receptors, Antigen, T-Cell, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, T-Lymphocyte Subsets, Immunotherapy, Adoptive, CD4-CD8 Ratio, Disease-Free Survival, Tumor Burden, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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