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

Standard

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, Jahrgang 126, Nr. 6, 01.06.2016, S. 2123-38.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Turtle, CJ, Hanafi, L-A, Berger, C, Gooley, TA, Cherian, S, Hudecek, M, Sommermeyer, D, Melville, K, Pender, B, Budiarto, TM, Robinson, E, Steevens, NN, Chaney, C, Soma, L, Chen, X, Yeung, C, Wood, B, Li, D, Cao, J, Heimfeld, S, Jensen, MC, Riddell, SR & Maloney, DG 2016, 'CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients', J CLIN INVEST, Jg. 126, Nr. 6, S. 2123-38. https://doi.org/10.1172/JCI85309

APA

Turtle, C. J., Hanafi, L-A., Berger, C., Gooley, T. A., Cherian, S., Hudecek, M., Sommermeyer, D., Melville, K., Pender, B., Budiarto, T. M., Robinson, E., Steevens, N. N., Chaney, C., Soma, L., Chen, X., Yeung, C., Wood, B., Li, D., Cao, J., ... Maloney, D. G. (2016). CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J CLIN INVEST, 126(6), 2123-38. https://doi.org/10.1172/JCI85309

Vancouver

Turtle CJ, Hanafi L-A, Berger C, Gooley TA, Cherian S, Hudecek M et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J CLIN INVEST. 2016 Jun 1;126(6):2123-38. https://doi.org/10.1172/JCI85309

Bibtex

@article{5478bbf449714414904fdb4f16e258b5,
title = "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.",
keywords = "Adult, Aged, CD4-CD8 Ratio, Disease-Free Survival, Humans, Immunotherapy, Adoptive/adverse effects, Lymphocyte Depletion/methods, Middle Aged, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/immunology, Receptors, Antigen, T-Cell/immunology, T-Lymphocyte Subsets/immunology, Tumor Burden/immunology, Young Adult",
author = "Turtle, {Cameron J} and La{\"i}la-A{\"i}cha Hanafi and Carolina Berger and Gooley, {Theodore A} and Sindhu Cherian and Michael Hudecek and Daniel Sommermeyer and Katherine Melville and Barbara Pender and Budiarto, {Tanya M} and Emily Robinson and Steevens, {Natalia N} and Colette Chaney and Lorinda Soma and Xueyan Chen and Cecilia Yeung and Brent Wood and Daniel Li and Jianhong Cao and Shelly Heimfeld and Jensen, {Michael C} and Riddell, {Stanley R} and Maloney, {David G}",
year = "2016",
month = jun,
day = "1",
doi = "10.1172/JCI85309",
language = "English",
volume = "126",
pages = "2123--38",
journal = "J CLIN INVEST",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "6",

}

RIS

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 -