CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
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CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. / Turtle, Cameron J; Hanafi, Laïla-Aïcha; Berger, Carolina; Gooley, Theodore A; Cherian, Sindhu; Hudecek, Michael; Sommermeyer, Daniel; Melville, Katherine; Pender, Barbara; Budiarto, Tanya M; Robinson, Emily; Steevens, Natalia N; Chaney, Colette; Soma, Lorinda; Chen, Xueyan; Yeung, Cecilia; Wood, Brent; Li, Daniel; Cao, Jianhong; Heimfeld, Shelly; Jensen, Michael C; Riddell, Stanley R; Maloney, David G.
In: J CLIN INVEST, Vol. 126, No. 6, 01.06.2016, p. 2123-38.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients
AU - Turtle, Cameron J
AU - Hanafi, Laïla-Aïcha
AU - Berger, Carolina
AU - Gooley, Theodore A
AU - Cherian, Sindhu
AU - Hudecek, Michael
AU - Sommermeyer, Daniel
AU - Melville, Katherine
AU - Pender, Barbara
AU - Budiarto, Tanya M
AU - Robinson, Emily
AU - Steevens, Natalia N
AU - Chaney, Colette
AU - Soma, Lorinda
AU - Chen, Xueyan
AU - Yeung, Cecilia
AU - Wood, Brent
AU - Li, Daniel
AU - Cao, Jianhong
AU - Heimfeld, Shelly
AU - Jensen, Michael C
AU - Riddell, Stanley R
AU - Maloney, David G
PY - 2016/6/1
Y1 - 2016/6/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - CD4-CD8 Ratio
KW - Disease-Free Survival
KW - Humans
KW - Immunotherapy, Adoptive/adverse effects
KW - Lymphocyte Depletion/methods
KW - Middle Aged
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology
KW - Receptors, Antigen, T-Cell/immunology
KW - T-Lymphocyte Subsets/immunology
KW - Tumor Burden/immunology
KW - Young Adult
U2 - 10.1172/JCI85309
DO - 10.1172/JCI85309
M3 - SCORING: Journal article
C2 - 27111235
VL - 126
SP - 2123
EP - 2138
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 6
ER -