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 Research and Public Health Oncology

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

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 7

Incorporation of Flu into Cy-based lymphodepletion increases the expansion and persistence of CAR–T cells.

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Incorporation of Flu into Cy-based lymphodepletion increases the expansi...
(A) Clinical outcomes of patients treated with CD19 CAR–T cells. (B) Graphs show the absolute count (top) and percentage (bottom) of EGFRt+ CAR–T cells in the CD3+CD4+ (left) and CD3+CD8+ (right) T cell subsets at intervals after CAR–T cell infusion in patients who received Cy and Flu lymphodepletion chemotherapy (DL2: Flu, n = 10) compared with those who received Cy alone or Cy/etoposide lymphodepletion (DL2: No Flu, n = 5). Day 0 represents a preinfusion sample and the background staining of the monoclonal antibody used to detect EGFRt+ T cells. All patients received EGFRt+ CAR–T cells at DL2. Data represent the mean ± SEM. The Mann-Whitney U test was used for statistical analysis. *P < 0.05; **P < 0.01. (C) The number of copies of integrated transgene (FlapEF1α copies/μg DNA) detected in PBMCs collected at the indicated times after the first CAR–T cell infusion in patients who received lymphodepletion with Cy/Flu (Flu, n = 17) compared with those who received Cy alone or Cy/etoposide (no Flu, n = 12). Time points after a second CAR–T cell infusion or allogeneic HCT are excluded. (D) DFS from the day of CAR–T cell infusion is shown for patients who received lymphodepletion with Cy/Flu (Flu, n = 17) compared with those who received Cy alone or Cy/etoposide (No Flu, n = 13). The median follow-up for Cy/Flu patients who were alive and in CR was 300 days. We compared the group who received Cy/Flu lymphodepletion and the group who received Cy-based lymphodepletion without Flu using the log-rank test, where P = 0.001.