CD19 CAR–T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
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
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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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 5

CAR–T cells are detected at higher levels in blood from patients with high tumor burden.

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CAR–T cells are detected at higher levels in blood from patients with hi...
(A) The 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 in blood at intervals after CAR–T cell infusion in patients with high (≥ 5% BM blasts by flow cytometry; n = 15) or low (< 5% BM blasts by flow cytometry; n = 5) BM disease burden prior to incorporation of risk-adjusted CAR–T cell dosing. Data represent the mean ± SEM. The Mann-Whitney U test was used for statistical analysis. *P < 0.05; **P < 0.01. (B) ImmunoSEQ analysis of the TCRB genes of CAR–T cells sorted from blood of treated patients demonstrates polyclonality of CD4+ (left) and CD8+ (right) CAR–T cells in the recipient after adoptive transfer and sharing of sequences between the infusion product and the recipient after adoptive transfer. Each point represents 1 detected TCRB gene sequence. The axes indicate the percentage of TCRB reads. TCRB sequences identified by points in red were detected only in the infused CAR–T cell product (x axes). TCRB sequences identified by points in green are detected only in the recipient at the indicated day after CAR–T cell infusion (y axes). TCRB sequences identified by points in blue are detected both in the infused CAR–T cell product and in the recipient at the indicated day after infusion.