CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia

Renier J. Brentjens, Marco L. Davila, Isabelle Riviere, Jae Park, Xiuyan Wang, Lindsay G. Cowell, Shirley Bartido, Jolanta Stefanski, Clare Taylor, Malgorzata Olszewska, Oriana Borquez-Ojeda, Jinrong Qu, Teresa Wasielewska, Qing He, Yvette Bernal, Ivelise V. Rijo, Cyrus Hedvat, Rachel Kobos, Kevin Curran, Peter Steinherz & 5 others Joseph Jurcic, Todd Rosenblat, Peter Maslak, Mark Frattini, Michel Sadelain

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Abstract

Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD- complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell-mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.

Original languageEnglish (US)
Article number177ra38
JournalScience Translational Medicine
Volume5
Issue number177
DOIs
StatePublished - Mar 20 2013

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Hematopoietic Stem Cell Transplantation
T-Lymphocytes
Residual Neoplasm
Drug Therapy
T-Cell Antigen Receptor
Antigen Receptors
B-Lymphocytes
Cytokines
Cell- and Tissue-Based Therapy
Therapeutics
High-Throughput Nucleotide Sequencing
Tumor Burden
Neoplasms
Steroids
Polymerase Chain Reaction
Survival

ASJC Scopus subject areas

  • Medicine(all)

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CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. / Brentjens, Renier J.; Davila, Marco L.; Riviere, Isabelle; Park, Jae; Wang, Xiuyan; Cowell, Lindsay G.; Bartido, Shirley; Stefanski, Jolanta; Taylor, Clare; Olszewska, Malgorzata; Borquez-Ojeda, Oriana; Qu, Jinrong; Wasielewska, Teresa; He, Qing; Bernal, Yvette; Rijo, Ivelise V.; Hedvat, Cyrus; Kobos, Rachel; Curran, Kevin; Steinherz, Peter; Jurcic, Joseph; Rosenblat, Todd; Maslak, Peter; Frattini, Mark; Sadelain, Michel.

In: Science Translational Medicine, Vol. 5, No. 177, 177ra38, 20.03.2013.

Research output: Contribution to journalArticle

Brentjens, RJ, Davila, ML, Riviere, I, Park, J, Wang, X, Cowell, LG, Bartido, S, Stefanski, J, Taylor, C, Olszewska, M, Borquez-Ojeda, O, Qu, J, Wasielewska, T, He, Q, Bernal, Y, Rijo, IV, Hedvat, C, Kobos, R, Curran, K, Steinherz, P, Jurcic, J, Rosenblat, T, Maslak, P, Frattini, M & Sadelain, M 2013, 'CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia', Science Translational Medicine, vol. 5, no. 177, 177ra38. https://doi.org/10.1126/scitranslmed.3005930
Brentjens, Renier J. ; Davila, Marco L. ; Riviere, Isabelle ; Park, Jae ; Wang, Xiuyan ; Cowell, Lindsay G. ; Bartido, Shirley ; Stefanski, Jolanta ; Taylor, Clare ; Olszewska, Malgorzata ; Borquez-Ojeda, Oriana ; Qu, Jinrong ; Wasielewska, Teresa ; He, Qing ; Bernal, Yvette ; Rijo, Ivelise V. ; Hedvat, Cyrus ; Kobos, Rachel ; Curran, Kevin ; Steinherz, Peter ; Jurcic, Joseph ; Rosenblat, Todd ; Maslak, Peter ; Frattini, Mark ; Sadelain, Michel. / CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. In: Science Translational Medicine. 2013 ; Vol. 5, No. 177.
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abstract = "Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD- complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell-mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.",
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AU - Brentjens, Renier J.

AU - Davila, Marco L.

AU - Riviere, Isabelle

AU - Park, Jae

AU - Wang, Xiuyan

AU - Cowell, Lindsay G.

AU - Bartido, Shirley

AU - Stefanski, Jolanta

AU - Taylor, Clare

AU - Olszewska, Malgorzata

AU - Borquez-Ojeda, Oriana

AU - Qu, Jinrong

AU - Wasielewska, Teresa

AU - He, Qing

AU - Bernal, Yvette

AU - Rijo, Ivelise V.

AU - Hedvat, Cyrus

AU - Kobos, Rachel

AU - Curran, Kevin

AU - Steinherz, Peter

AU - Jurcic, Joseph

AU - Rosenblat, Todd

AU - Maslak, Peter

AU - Frattini, Mark

AU - Sadelain, Michel

PY - 2013/3/20

Y1 - 2013/3/20

N2 - Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD- complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell-mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.

AB - Adults with relapsed B cell acute lymphoblastic leukemia (B-ALL) have a dismal prognosis. Only those patients able to achieve a second remission with no minimal residual disease (MRD) have a hope for long-term survival in the context of a subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have treated five relapsed B-ALL subjects with autologous T cells expressing a CD19-specific CD28/CD3ζ second-generation dual-signaling chimeric antigen receptor (CAR) termed 19-28z. All patients with persistent morphological disease or MRD+ disease upon T cell infusion demonstrated rapid tumor eradication and achieved MRD- complete remissions as assessed by deep sequencing polymerase chain reaction. Therapy was well tolerated, although significant cytokine elevations, specifically observed in those patients with morphologic evidence of disease at the time of treatment, required lymphotoxic steroid therapy to ameliorate cytokine-mediated toxicities. Indeed, cytokine elevations directly correlated to tumor burden at the time of CAR-modified T cell infusions. Tumor cells from one patient with relapsed disease after CAR-modified T cell therapy, who was ineligible for additional allo-HSCT or T cell therapy, exhibited persistent expression of CD19 and sensitivity to autologous 19-28z T cell-mediated cytotoxicity, which suggests potential clinical benefit of additional CAR-modified T cell infusions. These results demonstrate the marked antitumor efficacy of 19-28z CAR-modified T cells in patients with relapsed/refractory B-ALL and the reliability of this therapy to induce profound molecular remissions, forming a highly effective bridge to potentially curative therapy with subsequent allo-HSCT.

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