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CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
Cameron J. Turtle, … , Stanley R. Riddell, David G. Maloney
Cameron J. Turtle, … , Stanley R. Riddell, David G. Maloney
Published April 25, 2016
Citation Information: J Clin Invest. 2016;126(6):2123-2138. https://doi.org/10.1172/JCI85309.
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Clinical Medicine Oncology

CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients

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Abstract

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.

Authors

Cameron J. Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Theodore A. Gooley, Sindhu Cherian, Michael Hudecek, Daniel Sommermeyer, Katherine Melville, Barbara Pender, Tanya M. Budiarto, Emily Robinson, Natalia N. Steevens, Colette Chaney, Lorinda Soma, Xueyan Chen, Cecilia Yeung, Brent Wood, Daniel Li, Jianhong Cao, Shelly Heimfeld, Michael C. Jensen, Stanley R. Riddell, David G. Maloney

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Figure 1

Heterogeneity in distribution of TN, TCM, and TEM/EMRA cells within CD4+ and CD8+ T cell subsets in normal donors and patients with B-ALL.

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Heterogeneity in distribution of TN, TCM, and TEM/EMRA cells within CD4+...
(A) Study participant flow chart. (B) Representative flow cytometry plots showing the immunophenotype of T cell subsets in blood from a B-ALL patient are shown. TN (CD45RA+CD62L+), TCM (CD45RA–CD62L+), and TEM/EMRA (CD62L–) cells can be identified in the CD3+CD4+ and CD3+CD8+ T cell populations. (C) The absolute CD4+ and CD8+ T cell counts in blood from healthy individuals (n = 14) and B-ALL patients (n = 30) are shown. Mann-Whitney U test was used for statistical analysis. (D) The percentages of TN, TCM, and TEM/EMRA cells in the CD3+CD4+ T cell population are shown. (E) The percentages of TN, TCM, and TEM/EMRA cells in the CD3+CD8+ T cell population are shown.
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