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3476 Long Term Follow-up after Treatment with Allogeneic Off-the-Shelf CAR T Cell Therapy for Relapsed or Refractory B-Cell Malignancies

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Biological therapies, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Therapies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Sanam Shahid, MD1, Georgia C Flynn1*, Audrey Mauguen, PhD2*, Jennifer Bieler1*, Susan E Prockop, MD3*, Andromachi Scaradavou, MD1, Jaap Jan Boelens, MD1, Craig S Sauter, MD4, Miguel-Angel Perales, MD5, Sergio A. Giralt, MD, FACP6, Xiuyan Wang, PhD7*, Isabelle Riviere, PhD7, Michel Sadelain, MD PhD8, Renier Brentjens, MD PhD9, Nancy A Kernan, MD1, Richard J O'Reilly, MD1* and Kevin J Curran, MD1

1Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
2Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
3Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
4Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
5Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
6Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
7Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY
8Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY
9Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY

CAR T cells provide benefit in patients with relapsed/refractory (R/R) hematologic malignancies. However, limitations of autologous products include cost, production complexity, quality of T cells, and life-threatening toxicity. To overcome these limitations, we developed allogeneic, “off-the-shelf” CD19-specific CAR T cells by transducing our institutional second-generation CD28-containing CAR (19-28z) into Epstein-Barr Virus (EBV)-specific cytotoxic lymphocytes (19-28z CAR EBV-CTLs).

Patients with R/R B-cell malignancies were stratified into 3 treatment cohorts: cohort 1 (disease recurrence after allogeneic or autologous hematopoietic cell transplant (HCT)), cohort 2 (19-28z CAR EBV-CTLs as consolidative therapy after autologous HCT), or cohort 3 (19-28z CAR EBV-CTLs as consolidative therapy after allogeneic HCT). The objectives were determining dose limiting toxicity (DLT; primary endpoint) and optimal dose for multiple infusions.

Sixteen patients were treated with 19-28z CAR EBV-CTLs with 8 in cohort 1 (B-ALL n=6; Burkitt lymphoma n=1; CLL n=1), 6 in cohort 2 (PMBCL n=2; DLBCL n=3; marginal zone lymphoma n=1), and 2 in cohort 3 (DLBCL n=2). Median age at treatment was 30 years (range 1-71 years). All patients were heavily pretreated, receiving a median of 5 lines of therapy (including any HCT received; range 3-11 lines of therapy) prior to 19-28z CAR EBV-CTLs. Dosing on this protocol was based off T cells/kg: median dose infused was 3x106 T cells/kg (range 1-10x106 T cells/kg). Twelve patients received multiple doses (overall median 2.5; range 1-3) with 3x106 T cells/kg determined to be the optimal dose enabling multiple treatments per manufactured cell line. Products had variable transduction efficiencies with a median of 28.7% (range 7.4-41%), and median 19-28z CAR EBV-CTL dose was 0.7x106/kg (range 0.05-2.7x106/kg). 19-28z CAR EBV-CTL sources were primary HCT donors (n=4) and third-party donors (n=12). HLA matching between patients and donors was 10/10 (n=3), 6/10 (n=2), 5/10 (n=1), 4/10 (n=3), and 2/10 (n=7). Ten of the patients were EBV-seropositive, four were seronegative, and two were serostatus unknown.

Severe cytokine release syndrome (CRS) or neurotoxicity did not occur post-infusion, and no DLT was noted in the trial. Six patients developed diffuse skin rash with 3 patients’ rashes deemed to be graft-versus-host disease (n=1 HLA-matched HCT donor; n=2 third-party donor), which resolved with topical steroids (n = 3). Median follow-up was 53.3 months (range 4.2-135 months) with 4 deaths due to disease progression. Overall survival of all patients was 81% at 12 months and 74% at 24 months (Figure 1).

In summation, we successfully treated 16 patients with an allogeneic, “off-the-shelf” 19-28z CAR EBV-CTL product without significant toxicity. The manufacturing platform effectively overcomes many of the limitations of autologous CAR T cell products including cost, need for patient-specific manufacturing, and life-threatening toxicity. CAR EBV-CTLs also broaden the applicability of CAR T cell therapy for patients with insufficient circulating T cells to generate autologous products. This trial determined an optimal manufacturing dose of allogeneic CAR T cells to enable repeated dosing. In the cohort of heavily pre-treated patients, long-term outcomes following multiple infusions of 19-28z CAR EBV-CTLs were excellent. Allogeneic, “off-the-shelf” CAR EBV-CTLs provide a readily available therapy for patients with limited therapeutic options, and this trial demonstrates the safety of CAR T cell infusions as consolidation after HCT. This trial was registered at www.clinicaltrials.gov as NCT01430390.

Figure 1: Overall survival following 19-28z CAR EBV-CTLs of all patients by disease (A) and donor source (B).

Disclosures: Prockop: AlloVir: Research Funding; Atara: Research Funding; Jasper: Research Funding; Pierre Fabre: Consultancy; CellEvolve: Consultancy; VOR: Consultancy; Regeneron: Honoraria. Boelens: Advanced Clinical: Honoraria; Immusoft: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Omeros: Consultancy, Honoraria; Bluerock: Consultancy, Honoraria; Bluebird Bio: Honoraria; SmartImmune: Consultancy, Honoraria. Sauter: Kite/a Gilead Company, Celgene/BMS, Gamida Cell, Karyopharm Therapeutics, Ono Pharmaceuticals, MorphoSys, CSL Behring, Syncopation Life Sciences, CRISPR Therapeutics and GSK.: Consultancy; Juno Therapeutics, Celgene/BMS, Bristol-Myers Squibb, Precision Biosciences, Actinium Pharmaceuticals, Sanofi-Genzyme and NKARTA.: Research Funding. Perales: Adicet: Honoraria; Equillium: Consultancy, Honoraria; Omeros: Consultancy, Current equity holder in publicly-traded company, Honoraria; Kite: Consultancy, Honoraria, Research Funding; DSMB: Other; Orcabio: Consultancy, Current equity holder in publicly-traded company, Honoraria; Takeda: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Cidara Therapeutics: Consultancy, Other; Exevir: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Celgene: Honoraria; Syncopation: Honoraria; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; VectivBio AG: Consultancy, Honoraria; Medigene: Consultancy, Other; NexImmune: Consultancy, Current equity holder in publicly-traded company; Miltenyi Biotec: Honoraria; Nektar Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy; Servier: Other; Karyopharm: Consultancy, Honoraria; Sellas Life Sciences: Consultancy; Astellas: Consultancy, Honoraria; Vor Biopharma: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Caribou: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Allogene: Research Funding; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Giralt: Amgen, Actinuum, Celgene/BMS, Kite Pharma, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Novartis, Spectrum Pharma, Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen, Actinuum, Celgene/BMS, Omeros, Johnson & Johnson, Miltenyi, Takeda: Research Funding. Riviere: Takeda: Current Employment. Sadelain: Mnemo: Current equity holder in private company, Research Funding; Minerva: Current equity holder in private company; Takeda: Research Funding; Fate: Research Funding; Atara: Research Funding. Brentjens: R.J.B. has licensed intellectual property to and collect royalties from BMS, Caribou and Sanofi. R.J.B. received research funding from BMS. R.J.B. is a consultant to BMS, Atara Biotherapeutics Inc, Coimmune, Triumvira and was a consultant for Gracell Bi: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: BMS, Caribou and Sanofi, Research Funding. Kernan: Amgen: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company. O'Reilly: Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Curran: Novartis: Consultancy, Research Funding; Celgene: Research Funding; Cellectis: Research Funding; Atara: Consultancy, Research Funding; Turn Bio: Consultancy.

*signifies non-member of ASH