Safety and Efficacy of Fully Human BCMA CAR T Cells in Combination with a Gamma Secretase Inhibitor to Increase BCMA Surface Expression in Patients with Relapsed or Refractory Multiple Myeloma
Authors: Cowan Andrew J. , Pont Margot , Sather Blythe Duke , Turtle Cameron J. , Till Brian G. , Libby Edward , Coffey David G. , Tuazon Sherilyn A. , Wood Brent L. , Gooley Ted A , Wu Qian Vicky , Shadman Mazyar , Gauthier Jordan , Chapuis Aude G. , Milano Filippo , Maloney David G. , Riddell Stanley R. , Green Damian J. 
Published: November 2021

Abstract
Background:
Chimeric antigen receptor T cells (CAR T cells) targeting B cell maturation antigen (BCMA) have demonstrated rapid and deep responses among patients with multi-agent refractory multiple myeloma (MM). BCMA is shed from tumor cells mediated through enzymatic cleavage by the gamma secretase complex, and tumor cells with low levels of BCMA could potentially escape CAR T recognition. We showed previously that gamma secretase inhibitors (GSI) increase BCMA surface density on tumor cells, decrease soluble BCMA levels, and enhance efficacy of BCMA CAR T cells in an immunodeficient mouse model. We have completed accrual to a phase 1 first-in-human trial of escalating doses of BCMA targeted CAR T cells in combination with a GSI (JSMD194) for patients with relapsed or refractory multiple myeloma, and herein report results on the 18 patients accrued to this trial.
Methods:
Eligible patients had relapsed/refractory MM, with ≥ 10% plasma cells in the bone marrow by CD138 IHC, and measurable disease. CD8+ and CD4+ T cells were enriched by To assess the discrete impact of the GSI on plasma cell BCMA expression, patients received a GSI (JSMD194) monotherapy "run-in" consisting of three oral doses (25 mg) administered 48 hours apart over 5 days. A bone marrow sample was obtained on day 5 and BCMA expression was compared to baseline. Following lymphodepleting chemotherapy, BCMA CAR T cells were infused at a starting dose of 5 x 10 7 CAR+ cells, in combination with JSMD194 dosed orally at 25 mg thrice weekly for three weeks, starting on the day of CAR infusion.
Results:
From June 2018 to March 2021, 18 patients underwent leukapheresis, run-in with JSMD194, and treatment with BCMA CAR T cells. The median age was 65 years, and patients had received a median of 10 prior lines of therapy (range, 4-19). 67% of patients were refractory to lenalidomide, pomalidomide, bortezomib, carfilzomib, and daratumumab, 72% had high-risk cytogenetic features, and 28% had extramedullary disease. 7/18 (39%) had prior BCMA targeted therapy; other BCMA targeted CAR T cell products had previously been administered to 4/18 patients (22%). All 18 treated patients completed the 5-day run-in with JSMD194. After three oral doses of GSI, increased from a median of 610 to 9563 receptors per cell, or a median of 12-fold (range, 0.2-fold to 157-fold; Figure 1). The only patient that did not demonstrate an increase in BCMA ABC after GSI run-in had previously received BCMA targeted therapy and BCMA expression at screening was virtually absent. 5 patients were treated at 5x10 7 CAR+ cells, 3 were treated at 15x10 7 CAR+ cells, 3 were treated at 30x10 7 CAR+ cells, and 7 were treated at 45x10 7 CAR+ cells dose levels. Treatment was consistent with other BCMA CAR T therapy, with manageable toxicities. One patient experienced a DLT. 95% of patients experienced cytokine release syndrome (CRS), mostly grade 1-2 (83%), and 66% of patients experienced ICANS, predominantly grades 1-2. The overall response rate was 89%, with 14 patients achieving ≥ VGPR, and 8 patients achieving CR (including 5 with sCR). Deep responses were observed at all dose levels; including the first patient treated on trial at (dose level 1) who has maintained a stringent CR (sCR) for over 35 months and 3 of 5 patients at dose level 1 had no evidence of progressive disease for &gt;18 months. With a median follow-up of 20 months, the median PFS is 11 months (95% CI, 6 mos to not reached). Amongst patients without prior exposure to BCMA targeted therapy (n=11), the median PFS has not been reached, while amongst those previously exposed to BCMA targeted therapy (n=7), the median PFS was 2 months.
Discussion:
In this study combining a GSI with BCMA CAR T cells, we have demonstrated that the combination is safe and tolerable. GSI administration routinely increased BCMA surface density on plasma cells. Further, we have observed durable, rapid responses in a heavily pretreated refractory population of MM patients, of whom a significant proportion had prior treatment with BCMA targeted therapy and CAR T therapy. The combination of BCMA CAR T and GSI may augment anti-tumor activity, even when very low doses of BCMA CAR T cells are administered.
Figure 1 Figure 1.

Disclosures
Cowan: Harpoon: Research Funding; Secura Bio: Consultancy; Sanofi Aventis: Consultancy, Research Funding; GSK: Consultancy; Abbvie: Consultancy, Research Funding; Nektar: Research Funding; Cellectar: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Research Funding. Pont: Lyell Immunopharma: Other: Has equity interest; SpringWorks Therapeutics: Other: Received consulting income; CellPoint B.V.: Current Employment. Sather: Lyell Immunopharma: Current Employment. Turtle: Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; PACT Pharma: Consultancy; Amgen: Consultancy; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; AstraZeneca: Consultancy, Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; TCR2 Therapeutics: Research Funding; T-CURX: Other: Scientific Advisory Board; Asher Bio: Consultancy; Allogene: Consultancy; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Nektar Therapeutics: Consultancy, Research Funding; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Libby: GSK: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Genentech: Research Funding. Tuazon: BMS: Current Employment. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Chapuis: Karkinos Therapeutics: Other: Ownership; Lonza: Other: Intellectual Property; Cullian: Other: Intellectual Property; TScan Therapeutics, Inc.: Consultancy, Other: Ownership; SignalOne Bio: Consultancy, Other: Ownership; Bluebird bio: Other: Intellectual Property; Juno therapeutics: Other: Intellectual Property; Adapyive Biotechnologies Corporation: Other: Ownership/Intellectual Property; Pfizer: Other: Intellectual Property; Affini-T: Other: Ownership; Ridgeline: Consultancy; BioNTech: Consultancy. Maloney: MorphoSys: Honoraria; Genentech: Honoraria; Navan Technologies: Honoraria, Other: Stock options; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Novartis: Honoraria; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Celgene: Other: Research funding was paid to my institution, Research Funding; Amgen: Honoraria; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Umoja: Honoraria; Legend Biotech: Honoraria; A2 Biotherapeutics: Honoraria, Other: Stock options; Janssen: Honoraria. Riddell: Lyell Immunopharma: Other. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding.

OffLabel Disclosure:
JSMD194 - an oral gamma secretase inhibitor