BACKGROUND: Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS: We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required. RESULTS: CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product. CONCLUSION: CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients. TRIAL REGISTRATION: NCT02546167. FUNDING: University of Pennsylvania-Novartis Alliance and NIH.
BACKGROUND: Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS: We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required. RESULTS:CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product. CONCLUSION:CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients. TRIAL REGISTRATION: NCT02546167. FUNDING: University of Pennsylvania-Novartis Alliance and NIH.
Entities:
Keywords:
Cancer immunotherapy; Clinical Trials; Oncology
Authors: James N Kochenderfer; Mark E Dudley; Sadik H Kassim; Robert P T Somerville; Robert O Carpenter; Maryalice Stetler-Stevenson; James C Yang; Giao Q Phan; Marybeth S Hughes; Richard M Sherry; Mark Raffeld; Steven Feldman; Lily Lu; Yong F Li; Lien T Ngo; Andre Goy; Tatyana Feldman; David E Spaner; Michael L Wang; Clara C Chen; Sarah M Kranick; Avindra Nath; Debbie-Ann N Nathan; Kathleen E Morton; Mary Ann Toomey; Steven A Rosenberg Journal: J Clin Oncol Date: 2014-08-25 Impact factor: 44.544
Authors: Syed Abbas Ali; Victoria Shi; Irina Maric; Michael Wang; David F Stroncek; Jeremy J Rose; Jennifer N Brudno; Maryalice Stetler-Stevenson; Steven A Feldman; Brenna G Hansen; Vicki S Fellowes; Frances T Hakim; Ronald E Gress; James N Kochenderfer Journal: Blood Date: 2016-07-13 Impact factor: 22.113
Authors: Cameron J Turtle; Laïla-Aïcha Hanafi; Carolina Berger; Theodore A Gooley; Sindhu Cherian; Michael Hudecek; Daniel Sommermeyer; Katherine Melville; Barbara Pender; Tanya M Budiarto; Emily Robinson; Natalia N Steevens; Colette Chaney; Lorinda Soma; Xueyan Chen; Cecilia Yeung; Brent Wood; Daniel Li; Jianhong Cao; Shelly Heimfeld; Michael C Jensen; Stanley R Riddell; David G Maloney Journal: J Clin Invest Date: 2016-04-25 Impact factor: 14.808
Authors: Dalia A Salem; Irina Maric; Constance M Yuan; David J Liewehr; David J Venzon; James Kochenderfer; Maryalice Stetler-Stevenson Journal: Leuk Res Date: 2018-07-18 Impact factor: 3.156
Authors: Robert O Carpenter; Moses O Evbuomwan; Stefania Pittaluga; Jeremy J Rose; Mark Raffeld; Shicheng Yang; Ronald E Gress; Frances T Hakim; James N Kochenderfer Journal: Clin Cancer Res Date: 2013-01-23 Impact factor: 12.531
Authors: Michael C Milone; Jonathan D Fish; Carmine Carpenito; Richard G Carroll; Gwendolyn K Binder; David Teachey; Minu Samanta; Mehdi Lakhal; Brian Gloss; Gwenn Danet-Desnoyers; Dario Campana; James L Riley; Stephan A Grupp; Carl H June Journal: Mol Ther Date: 2009-04-21 Impact factor: 11.454
Authors: Shaji Kumar; Bruno Paiva; Kenneth C Anderson; Brian Durie; Ola Landgren; Philippe Moreau; Nikhil Munshi; Sagar Lonial; Joan Bladé; Maria-Victoria Mateos; Meletios Dimopoulos; Efstathios Kastritis; Mario Boccadoro; Robert Orlowski; Hartmut Goldschmidt; Andrew Spencer; Jian Hou; Wee Joo Chng; Saad Z Usmani; Elena Zamagni; Kazuyuki Shimizu; Sundar Jagannath; Hans E Johnsen; Evangelos Terpos; Anthony Reiman; Robert A Kyle; Pieter Sonneveld; Paul G Richardson; Philip McCarthy; Heinz Ludwig; Wenming Chen; Michele Cavo; Jean-Luc Harousseau; Suzanne Lentzsch; Jens Hillengass; Antonio Palumbo; Alberto Orfao; S Vincent Rajkumar; Jesus San Miguel; Herve Avet-Loiseau Journal: Lancet Oncol Date: 2016-08 Impact factor: 41.316
Authors: David T Teachey; Simon F Lacey; Pamela A Shaw; J Joseph Melenhorst; Shannon L Maude; Noelle Frey; Edward Pequignot; Vanessa E Gonzalez; Fang Chen; Jeffrey Finklestein; David M Barrett; Scott L Weiss; Julie C Fitzgerald; Robert A Berg; Richard Aplenc; Colleen Callahan; Susan R Rheingold; Zhaohui Zheng; Stefan Rose-John; Jason C White; Farzana Nazimuddin; Gerald Wertheim; Bruce L Levine; Carl H June; David L Porter; Stephan A Grupp Journal: Cancer Discov Date: 2016-04-13 Impact factor: 39.397
Authors: Aaron P Rapoport; Edward A Stadtmauer; Gwendolyn K Binder-Scholl; Olga Goloubeva; Dan T Vogl; Simon F Lacey; Ashraf Z Badros; Alfred Garfall; Brendan Weiss; Jeffrey Finklestein; Irina Kulikovskaya; Sanjoy K Sinha; Shari Kronsberg; Minnal Gupta; Sarah Bond; Luca Melchiori; Joanna E Brewer; Alan D Bennett; Andrew B Gerry; Nicholas J Pumphrey; Daniel Williams; Helen K Tayton-Martin; Lilliam Ribeiro; Tom Holdich; Saul Yanovich; Nancy Hardy; Jean Yared; Naseem Kerr; Sunita Philip; Sandra Westphal; Don L Siegel; Bruce L Levine; Bent K Jakobsen; Michael Kalos; Carl H June Journal: Nat Med Date: 2015-07-20 Impact factor: 53.440
Authors: Adam D Cohen; Alfred L Garfall; Ahmet Dogan; Simon F Lacey; Chris Martin; Nikoletta Lendvai; Dan T Vogl; Matthew Spear; Alexander M Lesokhin Journal: Blood Adv Date: 2019-08-27
Authors: Alfred L Garfall; Ehren K Dancy; Adam D Cohen; Wei-Ting Hwang; Joseph A Fraietta; Megan M Davis; Bruce L Levine; Don L Siegel; Edward A Stadtmauer; Dan T Vogl; Adam Waxman; Aaron P Rapoport; Michael C Milone; Carl H June; J Joseph Melenhorst Journal: Blood Adv Date: 2019-10-08