CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
Phase 2 or 3 results paper on CD19 in Acute lymphoblastic leukaemia, in Journal of Clinical Investigation (2016), one of the most cited Europe PMC records with CD19 in its title.
Overview
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.
Indexed on Europe PMC as PubMed record 27111235 (DOI 10.1172/jci85309). Its title names CD19 and its text names Acute lymphoblastic leukaemia; PubMed types it as a clinical trial report (Clinical Trial, Phase II, Research Support, Non-U.S. Gov't, research-article, Clinical Trial, Phase I, Research Support, N.I.H., Extramural). It was matched automatically to the idea "Hospital-based CAR-T manufacturing at cost through a public network" and no figure has been checked by an editor.
One of the most cited trial reports Europe PMC returns for CD19 in Acute lymphoblastic leukaemia, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
- Matched by CD19 in the title and Acute lymphoblastic leukaemia in the title or abstract of the Europe PMC record; the summary reproduces the record's abstract and no figure has been verified against the full paper.
- Chosen as a phase 2 or 3 report by the record's publication type or its own wording, not by reading the paper.
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