T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults

A phase 1 dose-escalation trial

Daniel W. Lee, James N. Kochenderfer, Maryalice Stetler-Stevenson, Yongzhi K. Cui, Cindy Delbrook, Steven A. Feldman, Terry J. Fry, Rimas Orentas, Marianna Sabatino, Nirali N. Shah, Seth M. Steinberg, Dave Stroncek, Nick Tschernia, Constance Yuan, Hua Zhang, Ling Zhang, Steven A. Rosenberg, Alan S. Wayne, Crystal L. Mackall

Research output: Contribution to journalArticle

Abstract

Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3-+-3 design to establish the maximum tolerated dose, patients received either 1-×-106 CAR-transduced T cells per kg (dose 1), 3-×-106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1-×-106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.

Original languageEnglish (US)
Pages (from-to)517-528
Number of pages12
JournalThe Lancet
Volume385
Issue number9967
DOIs
StatePublished - Feb 7 2015
Externally publishedYes

Fingerprint

CD19 Antigens
Antigen Receptors
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Young Adult
T-Lymphocytes
Maximum Tolerated Dose
T-Cell Antigen Receptor
B-Lymphocytes
Fever
Cytokines
Single-Chain Antibodies
Hypokalemia
Hematopoietic Stem Cell Transplantation
National Institutes of Health (U.S.)
B-Cell Lymphoma
Financial Management
B-Cell Chronic Lymphocytic Leukemia
Cell- and Tissue-Based Therapy
Neutropenia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lee, D. W., Kochenderfer, J. N., Stetler-Stevenson, M., Cui, Y. K., Delbrook, C., Feldman, S. A., ... Mackall, C. L. (2015). T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. The Lancet, 385(9967), 517-528. https://doi.org/10.1016/S0140-6736(14)61403-3

T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults : A phase 1 dose-escalation trial. / Lee, Daniel W.; Kochenderfer, James N.; Stetler-Stevenson, Maryalice; Cui, Yongzhi K.; Delbrook, Cindy; Feldman, Steven A.; Fry, Terry J.; Orentas, Rimas; Sabatino, Marianna; Shah, Nirali N.; Steinberg, Seth M.; Stroncek, Dave; Tschernia, Nick; Yuan, Constance; Zhang, Hua; Zhang, Ling; Rosenberg, Steven A.; Wayne, Alan S.; Mackall, Crystal L.

In: The Lancet, Vol. 385, No. 9967, 07.02.2015, p. 517-528.

Research output: Contribution to journalArticle

Lee, DW, Kochenderfer, JN, Stetler-Stevenson, M, Cui, YK, Delbrook, C, Feldman, SA, Fry, TJ, Orentas, R, Sabatino, M, Shah, NN, Steinberg, SM, Stroncek, D, Tschernia, N, Yuan, C, Zhang, H, Zhang, L, Rosenberg, SA, Wayne, AS & Mackall, CL 2015, 'T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial', The Lancet, vol. 385, no. 9967, pp. 517-528. https://doi.org/10.1016/S0140-6736(14)61403-3
Lee, Daniel W. ; Kochenderfer, James N. ; Stetler-Stevenson, Maryalice ; Cui, Yongzhi K. ; Delbrook, Cindy ; Feldman, Steven A. ; Fry, Terry J. ; Orentas, Rimas ; Sabatino, Marianna ; Shah, Nirali N. ; Steinberg, Seth M. ; Stroncek, Dave ; Tschernia, Nick ; Yuan, Constance ; Zhang, Hua ; Zhang, Ling ; Rosenberg, Steven A. ; Wayne, Alan S. ; Mackall, Crystal L. / T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults : A phase 1 dose-escalation trial. In: The Lancet. 2015 ; Vol. 385, No. 9967. pp. 517-528.
@article{1c01fb1cf6fd4424ac75c81eaa689104,
title = "T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial",
abstract = "Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3-+-3 design to establish the maximum tolerated dose, patients received either 1-×-106 CAR-transduced T cells per kg (dose 1), 3-×-106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90{\%} feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1-×-106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14{\%}) of 21 patients (95{\%} CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43{\%}] of 21 patients), hypokalaemia (nine [43{\%}] of 21 patients), fever and neutropenia (eight [38{\%}] of 21 patients), and cytokine release syndrome (three [14{\%}) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.",
author = "Lee, {Daniel W.} and Kochenderfer, {James N.} and Maryalice Stetler-Stevenson and Cui, {Yongzhi K.} and Cindy Delbrook and Feldman, {Steven A.} and Fry, {Terry J.} and Rimas Orentas and Marianna Sabatino and Shah, {Nirali N.} and Steinberg, {Seth M.} and Dave Stroncek and Nick Tschernia and Constance Yuan and Hua Zhang and Ling Zhang and Rosenberg, {Steven A.} and Wayne, {Alan S.} and Mackall, {Crystal L.}",
year = "2015",
month = "2",
day = "7",
doi = "10.1016/S0140-6736(14)61403-3",
language = "English (US)",
volume = "385",
pages = "517--528",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9967",

}

TY - JOUR

T1 - T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults

T2 - A phase 1 dose-escalation trial

AU - Lee, Daniel W.

AU - Kochenderfer, James N.

AU - Stetler-Stevenson, Maryalice

AU - Cui, Yongzhi K.

AU - Delbrook, Cindy

AU - Feldman, Steven A.

AU - Fry, Terry J.

AU - Orentas, Rimas

AU - Sabatino, Marianna

AU - Shah, Nirali N.

AU - Steinberg, Seth M.

AU - Stroncek, Dave

AU - Tschernia, Nick

AU - Yuan, Constance

AU - Zhang, Hua

AU - Zhang, Ling

AU - Rosenberg, Steven A.

AU - Wayne, Alan S.

AU - Mackall, Crystal L.

PY - 2015/2/7

Y1 - 2015/2/7

N2 - Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3-+-3 design to establish the maximum tolerated dose, patients received either 1-×-106 CAR-transduced T cells per kg (dose 1), 3-×-106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1-×-106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.

AB - Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1-30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3-+-3 design to establish the maximum tolerated dose, patients received either 1-×-106 CAR-transduced T cells per kg (dose 1), 3-×-106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov, number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1-×-106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0-36·3). The most common non-haematological grade 3 adverse events were fever (nine [43%] of 21 patients), hypokalaemia (nine [43%] of 21 patients), fever and neutropenia (eight [38%] of 21 patients), and cytokine release syndrome (three [14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.

UR - http://www.scopus.com/inward/record.url?scp=84923019006&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923019006&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(14)61403-3

DO - 10.1016/S0140-6736(14)61403-3

M3 - Article

VL - 385

SP - 517

EP - 528

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9967

ER -