T cells genetically modified to express an anti–B-Cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma

Jennifer N. Brudno, Irina Maric, Steven D. Hartman, Jeremy J. Rose, Michael Wang, Norris Lam, Maryalice Stetler-Stevenson, Dalia Salem, Constance Yuan, Steven Pavletic, Jennifer A. Kanakry, Syed Abbas Ali, Lekha Mikkilineni, Steven A. Feldman, David F. Stroncek, Brenna G. Hansen, Judith Lawrence, Rashmika Patel, Frances Hakim, Ronald E. GressJames N. Kochenderfer

Research output: Contribution to journalArticle

Abstract

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 3 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a g-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease–negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

Original languageEnglish (US)
Pages (from-to)2267-2280
Number of pages14
JournalJournal of Clinical Oncology
Volume36
Issue number22
DOIs
StatePublished - Aug 1 2018

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B-Cell Maturation Antigen
Antigen Receptors
Multiple Myeloma
T-Lymphocytes
Antigens
Bone Marrow
Plasmacytoma
Residual Neoplasm
Cell- and Tissue-Based Therapy
Plasma Cells
Cyclophosphamide
Disease-Free Survival
Therapeutics
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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T cells genetically modified to express an anti–B-Cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. / Brudno, Jennifer N.; Maric, Irina; Hartman, Steven D.; Rose, Jeremy J.; Wang, Michael; Lam, Norris; Stetler-Stevenson, Maryalice; Salem, Dalia; Yuan, Constance; Pavletic, Steven; Kanakry, Jennifer A.; Ali, Syed Abbas; Mikkilineni, Lekha; Feldman, Steven A.; Stroncek, David F.; Hansen, Brenna G.; Lawrence, Judith; Patel, Rashmika; Hakim, Frances; Gress, Ronald E.; Kochenderfer, James N.

In: Journal of Clinical Oncology, Vol. 36, No. 22, 01.08.2018, p. 2267-2280.

Research output: Contribution to journalArticle

Brudno, JN, Maric, I, Hartman, SD, Rose, JJ, Wang, M, Lam, N, Stetler-Stevenson, M, Salem, D, Yuan, C, Pavletic, S, Kanakry, JA, Ali, SA, Mikkilineni, L, Feldman, SA, Stroncek, DF, Hansen, BG, Lawrence, J, Patel, R, Hakim, F, Gress, RE & Kochenderfer, JN 2018, 'T cells genetically modified to express an anti–B-Cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma', Journal of Clinical Oncology, vol. 36, no. 22, pp. 2267-2280. https://doi.org/10.1200/JCO.2018.77.8084
Brudno, Jennifer N. ; Maric, Irina ; Hartman, Steven D. ; Rose, Jeremy J. ; Wang, Michael ; Lam, Norris ; Stetler-Stevenson, Maryalice ; Salem, Dalia ; Yuan, Constance ; Pavletic, Steven ; Kanakry, Jennifer A. ; Ali, Syed Abbas ; Mikkilineni, Lekha ; Feldman, Steven A. ; Stroncek, David F. ; Hansen, Brenna G. ; Lawrence, Judith ; Patel, Rashmika ; Hakim, Frances ; Gress, Ronald E. ; Kochenderfer, James N. / T cells genetically modified to express an anti–B-Cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. In: Journal of Clinical Oncology. 2018 ; Vol. 36, No. 22. pp. 2267-2280.
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abstract = "Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 3 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a g-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81{\%}, with 63{\%} very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease–negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.",
author = "Brudno, {Jennifer N.} and Irina Maric and Hartman, {Steven D.} and Rose, {Jeremy J.} and Michael Wang and Norris Lam and Maryalice Stetler-Stevenson and Dalia Salem and Constance Yuan and Steven Pavletic and Kanakry, {Jennifer A.} and Ali, {Syed Abbas} and Lekha Mikkilineni and Feldman, {Steven A.} and Stroncek, {David F.} and Hansen, {Brenna G.} and Judith Lawrence and Rashmika Patel and Frances Hakim and Gress, {Ronald E.} and Kochenderfer, {James N.}",
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TY - JOUR

T1 - T cells genetically modified to express an anti–B-Cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma

AU - Brudno, Jennifer N.

AU - Maric, Irina

AU - Hartman, Steven D.

AU - Rose, Jeremy J.

AU - Wang, Michael

AU - Lam, Norris

AU - Stetler-Stevenson, Maryalice

AU - Salem, Dalia

AU - Yuan, Constance

AU - Pavletic, Steven

AU - Kanakry, Jennifer A.

AU - Ali, Syed Abbas

AU - Mikkilineni, Lekha

AU - Feldman, Steven A.

AU - Stroncek, David F.

AU - Hansen, Brenna G.

AU - Lawrence, Judith

AU - Patel, Rashmika

AU - Hakim, Frances

AU - Gress, Ronald E.

AU - Kochenderfer, James N.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 3 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a g-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease–negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

AB - Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 3 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a g-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease–negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

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