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3872 Safety and Efficacy of Third Generation CD20 Targeted CAR-T (MB-106) for Treatment of Relapsed/Refractory B-NHL and CLL

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Clinical: Poster III
Hematology Disease Topics & Pathways:
Clinical Trials, Lymphoid Leukemias, Biological, Adults, CLL, Lymphomas, Non-Hodgkin Lymphoma, Clinical Research, B Cell Lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Indolent Lymphoma, Aggressive Lymphoma, Therapies, Immunotherapy, Lymphoid Malignancies, Study Population
Monday, December 13, 2021, 6:00 PM-8:00 PM

Mazyar Shadman, MD1,2,3, Cecilia Yeung, MD2, Mary Redman, PhD2*, Sang Yun Lee, Ph.D.4*, Dong Hoon Lee, B.S.4*, Susan Ra, BS2*, Chaitra S. Ujjani, MD1, Bruce J. Dezube, MD5*, Christina Poh, MD6, Edus H. Warren, MD, PhD1, Aude G. Chapuis, MD2, Damian J. Green, MD2,7, Andrew J. Cowan, MD2,8, Ryan D. Cassaday, MD9,10, Hans-Peter Kiem, MD PhD2,11, Jordan Gauthier, MD12,13, Cameron J. Turtle, MBBS, PhD7,12, Ryan C. Lynch, MD14, Stephen D. Smith, MD8,15, Ajay K Gopal, MD1,16, David G. Maloney, MD, PhD17 and Brian G. Till, MD8,16

1University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA
2Fred Hutchinson Cancer Research Center, Seattle, WA
3Division of Medical Oncology, Uw/Fred Hutchinson Cancer Research Center, Seattle, WA
4Fred Hutchinson Cancer Research Center, Seattle
5Mustang Bio, Worcester, MA
6Division of Medical Oncology, University of Washington, Seattle, WA
7Department of Medicine, University of Washington, Seattle, WA
8Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
9UW/FHCRC, Seattle, WA
10Department of Medicine, Division of Hematology, University of Washington, Seattle, WA
11University of Washington, Seattle, WA
12Clinical Research Division, Fred Hutchinson Cancer Research Ctr., Seattle, WA
13University of Washington, Seattle Cancer Care Alliance, Seattle, WA
14Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA
15Division of Medical Oncology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA
16University of Washington/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA
17Fred Hutchinson Cancer Rsrch. Ctr., Seattle, WA

Background: Autologous CD19-targeting chimeric antigen receptor T cell (CAR-T) products are approved as standard treatment options for patients (pts) with relapsed diffuse large cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). Their long-term efficacy for DLBCL is ~40% and is unknown for other histologies. Additionally, associated toxicities including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remain a challenge. CD20 is a proven target for treatment of B-NHLs/CLL with demonstrated high clinical efficacy of unmodified, radiolabeled, and bispecific antibodies. Therefore, CD20-targeted CAR-T represents a promising adoptive immunotherapy option that could be utilized to treat relapsed/refractory (R/R) B-NHLs and CLL. MB-106 is a fully human 3rd-generation CD20-targeted CAR-T product with both 4-1BB and CD28 costimulatory domains. We present results of our ongoing phase I/II clinical trial investigating safety and efficacy of CD20 CAR-T for high-risk B-NHLs and CLL (NCT03277729).

Methods: Pts with R/R CD20+ B-cell malignancies are eligible, including but not limited to DLBCL, FL, MCL, and CLL. Prior treatment with CD19 CAR-T is permitted. Lymphodepletion (LD) consists of cyclophosphamide (Cy) ± fludarabine (Flu). CAR-T cells are administered at one of 4 dose levels (DL): DL1: 3.3x105, DL2: 1x106, DL3: 3.3x106, DL4: 1x107 CAR T cells/kg. A continual reassessment method dose escalation design was used to find the maximally tolerated dose. CAR-T is infused in the outpatient setting except for the first pt of each dose cohort (overnight observation). Treatment response is assessed on day 28. CRS and ICANS are graded per ASTCT consensus grading. The study underwent a major cell manufacturing modification after treating 7 pts with no objective responses as previously reported (Shadman, ASH 2020, #1443). This abstract includes pts who were treated under the modified process.

Results: Between Dec 2019 and July 2021, 16 pts (12 FL, 2 MCL, 1 CLL, 1 DLBCL) were treated after LD with Cy-Flu and had day 28 assessment. All DLs were reached (see table), with no dose-limiting toxicities to date. CRS occurred in 7 pts (44%): 4 pts with grade (Gr) 1 and 3 with Gr 2. ICANS was observed in 1 pt (6.2%) at Gr 2. There were no Gr 3 or Gr 4 CRS or ICANS. Median time to CRS was 6.5 days (range, 0-12); the 1 ICANS event occurred on day 12. One pt (CLL) developed Gr 3 temporary neuropathic pain which, in the absence of other explanation, was attributed to the CAR-T. No pts had tumor lysis syndrome or Gr 3-4 infections. Thrombocytopenia (Gr 3-4: 19%) and neutropenia (Gr 3-4: 94%) were common but there were no bleeding complications, and the rate of febrile neutropenia was 19%.

Overall response (ORR) was 94% (15/16) with complete response (CR) rate of 62% (10/16). In FL pts (n =12), ORR was 92% (11/12) and CR rate was 75% (9/12). Among FL pts who received DL 3 or 4, the CR rate was 86%. The CLL pt had a PET-negative CR and undetectable measurable residual disease in peripheral blood and bone marrow by flow cytometry (10-4) (uMRD4) on day 28. The pt with DLBCL achieved a partial response (PR) on day 28 and a repeat PET on day ~ 90 showed continued improvement but still indicating a PR. Among pts who achieved a CR, only one pt (FL) relapsed after 9 months. All other CRs are ongoing (range: 3-18 months). CAR-T persistence was lost at day 95 in 1 pt who had progression and proceeded to other anti-lymphoma treatment; 2 other patients lost CAR-T engraftment by day 181 and 201 with B cell recovery. All other patients continue to have detectable CAR-T cells as of last follow-up (max 13 months post-infusion).

Conclusion: Treatment with MB-106 shows a favorable safety profile with no Gr 3 or Gr 4 CRS or ICANS. In addition, we observed a high rate of ORR and CR with ongoing CRs and high rate of CAR-T persistence. Enrollment is currently ongoing; data will be updated at the time of presentation.

Disclosures: 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. Yeung: Merck,Celgene: Consultancy. Ujjani: Atara, AstraZeneca, AbbVIe, ACDT, Epizyme, TG Therapeutics, Pharmacyclics, Beigene: Consultancy. Dezube: Mustang Bio: Current Employment, Current holder of individual stocks in a privately-held company. Poh: Acrotech: Honoraria; Morphosys: Consultancy; Incyte: 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. 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. Cowan: Abbvie: Consultancy, Research Funding; Harpoon: Research Funding; Janssen: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Nektar: Research Funding; GSK: Consultancy; Secura Bio: Consultancy; Cellectar: Consultancy. Cassaday: Amgen: Consultancy, Research Funding; Servier: Research Funding; Vanda Pharmaceuticals: Research Funding; Pfizer: Consultancy, Research Funding; Kite/Gilead: Consultancy, Honoraria, Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding. Kiem: Homology Medicines: Consultancy; VOR Biopharma: Consultancy; Ensoma Inc.: Consultancy, Current holder of individual stocks in a privately-held company. Gauthier: Eusapharma: Consultancy; JMP: Consultancy; Larvol: Consultancy; Multerra Bio: Consultancy; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, A BMS Company: Research Funding; Celgene, a BMS Company: Research Funding. Turtle: T-CURX: Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, 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; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; AstraZeneca: Consultancy, Research Funding; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Asher Bio: Consultancy; Amgen: Consultancy; PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Allogene: Consultancy. Lynch: Incyte: Research Funding; Cyteir: Research Funding; Morphosys: Consultancy; SeaGen: Research Funding; RAPT: Research Funding; Juno Therapetics: Research Funding; TG Therapeutics: Research Funding; Bayer: Research Funding; Genentech: Research Funding. Smith: Bayer: Research Funding; AstraZeneca: Consultancy, Research Funding; Ayala (spouse): Research Funding; Bristol Myers Squibb (spouse): Research Funding; Portola Pharmaceuticals: Research Funding; Merck Sharp & Dohme Corp: Research Funding; De Novo Biopharma: Research Funding; Acerta Pharma BV: Research Funding; Beigene: Consultancy, Research Funding; Millenium/Takeda: Consultancy; ADC Therapeutics: Consultancy; KITE pharm: Consultancy; Genentech: Research Funding; Incyte Corporation: Research Funding; Ignyta (spouse): Research Funding; Incyte: Consultancy; Karyopharm: Consultancy. Gopal: Karyopharm: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Incyte: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; MorphoSys: Honoraria; ADC Therapeutics: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Nurix Inc: Consultancy, Honoraria; Teva: Research Funding; Merck: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Astra-Zeneca: Research Funding; Takeda: Research Funding; Bristol Meyers Squibb: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Acrotech: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; IGM Biosciences: Research Funding; Cellectar: Consultancy, Honoraria; SeaGen: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria. Maloney: BioLineRx, Juno, Celgene, Kite, a Gilead Company, Gilead, Novartis, and Pharmacyclics: Honoraria; A2 Biotherapeutics: Consultancy; Kite, a Gilead Company, Juno, and Celgene: Research Funding; Juno: Patents & Royalties; A2 Biotherapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Till: Mustang Bio: Consultancy, Patents & Royalties, Research Funding.

*signifies non-member of ASH