Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma

被引:1320
作者
Raje, Noopur [1 ]
Berdeja, Jesus [6 ,7 ]
Lin, Yi [8 ]
Siegel, David [9 ]
Jagannath, Sundar [11 ]
Madduri, Deepu [11 ]
Liedtke, Michaela [12 ]
Rosenblatt, Jacalyn [2 ]
Maus, Marcela V. [1 ]
Turka, Ashley [5 ]
Lam, Lyh-Ping [5 ]
Morgan, Richard A. [5 ]
Friedman, Kevin [5 ]
Massaro, Monica [5 ]
Wang, Julie [10 ]
Russotti, Greg [10 ]
Yang, Zhihong [10 ]
Campbell, Timothy [13 ]
Hege, Kristen [13 ]
Petrocca, Fabio [5 ]
Quigley, M. Travis [5 ]
Munshi, Nikhil [3 ,4 ]
Kochenderfer, James N. [14 ]
机构
[1] Massachusetts Gen Hosp, Canc Ctr, Boston, MA USA
[2] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA
[3] Dana Farber Canc Inst, Boston, MA 02115 USA
[4] Vet Affairs Boston Healthcare Syst, Boston, MA USA
[5] Bluebird Bio, Cambridge, MA USA
[6] Sarah Cannon Res Inst, Nashville, TN USA
[7] Tennessee Oncol, Nashville, TN USA
[8] Mayo Clin, Rochester, MN USA
[9] Hackensack Univ, Med Ctr, Hackensack, NJ USA
[10] Celgene, Summit, NJ USA
[11] Mt Sinai Med Ctr, New York, NY 10029 USA
[12] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA
[13] Celgene, San Francisco, CA USA
[14] NCI, Expt Transplantat & Immunol Branch, NIH, Bldg 10,CRC Rm 3-3888, Bethesda, MD 20892 USA
关键词
B-CELL; MATURATION ANTIGEN; REMISSIONS; MULTICENTER; MANAGEMENT; SELINEXOR; KTE-C19;
D O I
10.1056/NEJMoa1817226
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. METHODS In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses of 50x10(6), 150x10(6), 450x10(6), or 800x10(6) CAR-positive (CAR+) T cells in the dose-escalation phase and 150x10(6) to 450x10(6) CAR+ T cells in the expansion phase. Patients had received at least three previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or were refractory to both drug classes. The primary end point was safety. RESULTS Results for the first 33 consecutive patients who received a bb2121 infusion are reported. The data-cutoff date was 6.2 months after the last infusion date. Hematologic toxic effects were the most common events of grade 3 or higher, including neutropenia (in 85% of the patients), leukopenia (in 58%), anemia (in 45%), and thrombocytopenia (in 45%). A total of 25 patients (76%) had cytokine release syndrome, which was of grade 1 or 2 in 23 patients (70%) and grade 3 in 2 patients (6%). Neurologic toxic effects occurred in 14 patients (42%) and were of grade 1 or 2 in 13 patients (39%). One patient (3%) had a reversible grade 4 neurologic toxic effect. The objective response rate was 85%, including 15 patients (45%) with complete responses. Six of the 15 patients who had a complete response have had a relapse. The median progression-free survival was 11.8 months (95% confidence interval, 6.2 to 17.8). All 16 patients who had a response (partial response or better) and who could be evaluated for minimal residual disease (MRD) had MRD-negative status (<= 10(-4) nucleated cells). CAR T-cell expansion was associated with responses, and CAR T cells persisted up to 1 year after the infusion. CONCLUSIONS We report the initial toxicity profile of a BCMA-directed cellular immunotherapy for patients with relapsed or refractory multiple myeloma. Antitumor activity was documented.
引用
收藏
页码:1726 / 1737
页数:12
相关论文
共 42 条
[1]   T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma [J].
Ali, Syed Abbas ;
Shi, Victoria ;
Maric, Irina ;
Wang, Michael ;
Stroncek, David F. ;
Rose, Jeremy J. ;
Brudno, Jennifer N. ;
Stetler-Stevenson, Maryalice ;
Feldman, Steven A. ;
Hansen, Brenna G. ;
Fellowes, Vicki S. ;
Hakim, Frances T. ;
Gress, Ronald E. ;
Kochenderfer, James N. .
BLOOD, 2016, 128 (13) :1688-1700
[2]  
[Anonymous], 2018, KYMR TIS
[3]  
[Anonymous], 2017, YESC AX CIL
[4]  
[Anonymous], 2006, GUID IND GEN THER CL
[5]   T Cells Genetically Modified to Express an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma [J].
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. .
JOURNAL OF CLINICAL ONCOLOGY, 2018, 36 (22) :2267-+
[6]   B-cell Maturation Antigen Is a Promising Target for Adoptive T-cell Therapy of Multiple Myeloma [J].
Carpenter, Robert O. ;
Evbuomwan, Moses O. ;
Pittaluga, Stefania ;
Rose, Jeremy J. ;
Raffeld, Mark ;
Yang, Shicheng ;
Gress, Ronald E. ;
Hakim, Frances T. ;
Kochenderfer, James N. .
CLINICAL CANCER RESEARCH, 2013, 19 (08) :2048-2060
[7]   Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma [J].
Chari, Ajai ;
Suvannasankha, Attaya ;
Fay, Joseph W. ;
Arnulf, Bertrand ;
Kaufman, Jonathan L. ;
Ifthikharuddin, Jainulabdeen J. ;
Weiss, Brendan M. ;
Krishnan, Amrita ;
Lentzsch, Suzanne ;
Comenzo, Raymond ;
Wang, Jianping ;
Nottage, Kerri ;
Chiu, Christopher ;
Khokhar, Nushmia Z. ;
Ahmadi, Tahamtan ;
Lonial, Sagar .
BLOOD, 2017, 130 (08) :974-981
[8]   Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia [J].
Chen, Christine ;
Siegel, David ;
Gutierrez, Martin ;
Jacoby, Meagan ;
Hofmeister, Craig C. ;
Gabrail, Nashat ;
Baz, Rachid ;
Mau-Sorensen, Morten ;
Berdeja, Jesus G. ;
Savona, Michael ;
Savoie, Lynn ;
Trudel, Suzanne ;
Areethamsirikul, Nuchanan ;
Unger, T. J. ;
Rashal, Tami ;
Hanke, Tim ;
Kauffman, Michael ;
Shacham, Sharon ;
Reece, Donna .
BLOOD, 2018, 131 (08) :855-863
[9]   Management of relapsed and refractory multiple myeloma: novel agents, antibodies, immunotherapies and beyond [J].
Chim, C. S. ;
Kumar, S. K. ;
Orlowski, R. Z. ;
Cook, G. ;
Richardson, P. G. ;
Gertz, M. A. ;
Giralt, S. ;
Mateos, M. V. ;
Leleu, X. ;
Anderson, K. C. .
LEUKEMIA, 2018, 32 (02) :252-262
[10]  
FDA, 2018, GUID IND CLIN TRIAL