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2005 Effective Cell Dose and Functional Attributes of Azercabtagene Zapreleucel (azer-cel; PBCAR0191) Associate with Allogeneic CAR T-Cell Safety and Efficacy in Patients with Relapsed/Refractory B-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, adult, Translational Research, Lymphomas, non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, immune mechanism, aggressive lymphoma, Therapies, immunology, Lymphoid Malignancies, Biological Processes, Study Population, Human
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Caron A. Jacobson, MD1, Tilanthi Jayawardena, PhD2*, Lou Yu, MS3*, Jason Hallman2*, Robert Schmittling2*, Erin Cuneo2*, Ian Belle, PhD2*, Gavin Sampey, PhD2*, Danica Cabral2*, Ashleigh Derrick2*, Josie Tueller2*, Koen Van Besien, MD, PhD4,5, Scott R. Solomon, MD6,7, Adam J. Olszewski, MD8,9, Joseph E. Maakaron, MD10,11, Ran Reshef, MD, MSc12,13, Anthony S. Stein, MD14, Abhinav Deol, MD15, Nitin Jain, MD16, Alan F. List, MD2 and Bijal D. Shah, MD17,18

1Dana-Farber Cancer Institute, Boston, MA
2Precision BioSciences, Inc., Durham, NC
3Clinical Operations, Precision BioSciences, Inc., Durham, NC
4Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY
5Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine/New York Presbyterian Hospital, New York, NY
6Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA
7Blood and Marrow Transplant Program, BMT Group of Georgia, Atlanta, GA
8Division of Hematology/Oncology, Brown University, Providence, RI
9Rhode Island Hospital, Providence, RI
10Division of Hematology, Oncology and Transplantation, University of Minnesota Medical Center, Minneapolis, MN
11Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
12Columbia Center for Translational Immunology, New York, NY
13Blood and Marrow Transplantation Program, Columbia University, New York, NY
14Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Duarte, CA
15Department of Oncology, Wayne State University/ Karmanos Cancer Institute, Detroit, MI
16Department of Leukemia, MD Anderson Cancer Center, Houston, TX
17H. Lee Moffitt Cancer Center, Tampa, FL
18Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Background: Characterization of product cellular attributes contributing to the in vivo expansion and toxicity of allogeneic, CD19-directed chimeric antigen receptor (CAR) T-cell therapy is necessary to optimize efficacy and safety. Using a single step process, the azer-cel CD19 CAR is knocked into the T-cell receptor alpha constant (TRAC) gene locus via a TRAC-specific ARCUS nuclease in activated T cells. Unlike autologous CAR T-cell therapy, all allogeneic CAR T products are cryopreserved. In this phase I study of the allogeneic, CD19-directed CAR T azer-cel, we analyzed post-thaw product attributes and cell composition of the infused product associated with pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcomes (NCT03666000).

Methods: Azer-cel was administered as a single infusion to 44 subjects across several dose levels and fludarabine/cyclophosphamide lymphodepletion regimens. CAR T cell peak expansion (Cmax), PK and area under the concentration-time curve (AUC) was assessed by flow cytometry and PD by multiplex cytokine assays. Azer-cel post-thaw cell composition was assessed by flow cytometry (minimally differentiated stem central memory [SCM], CC-chemokine receptor 7 (CCR7)+; differentiated effector memory, CCR7-). Effective cell number infused for any antigenically defined population was estimated using the product of the population percentage and the total post-thaw viable cell number. Overall tumor burden was measured as sum of the products of perpendicular diameters of target lesions and response was evaluated using Lugano 2016 criteria. Responders had either a complete or partial response at Day 28 or later. Relationships to safety events and efficacy were assessed using univariate correlative analyses (variables selected based on Pearson correlation coefficients ρ(rho)>0.35 unless specified, P-value <0.05).

Results: Peak azer-cel levels and AUC varied by dose level with median Cmax ranging from 38 cells/mL at DL2 to 6.7x 104 cells/mL at DL4b, whereas median AUC0-28 ranged between 3 x 102 to 5.1x 105(cells/mL*days). Both azer-cel Cmax and AUC correlated strongly with SCM cell dose (P=0.009 & P=0.0026, respectively). Development of cytokine release syndrome (CRS) associated with effective SCM CD8+ cell dose (P<0.05) and total tumor burden (P=0.0087), in addition to Cmax of the cytokines interleukin (IL)-6, TNFα, MIP1α, IL-10 and C-X-C motif chemokine ligand 10 (CXCL10) or Interferon gamma-induced protein 10 (IP10) (P<0.01). Immune effector cell-associated neurotoxicity syndrome (ICANS) correlated with azer-cel Cmax (P=0.035), AUC (P=0.0057), total tumor burden (P=0.004), and effective SCM CAR T cell dose (P<0.05), as well as changes in a distinct set of cytokines that included IL-2, IL-8, IIL-15, IL-6, and IP10 (P<0.05). Grade >3 ICANS correlated strongly with effective SCM CD4+ cell dose (P=0.0015), differentiated CD4+CCR7- cell dose (ρ =0.34, P=0.029) and CD4:CD8 ratio (ρ = 0.32, P= 0.036), in addition to Cmax of IL-6, IL-2 and IP10 (P< 0.01). Overall response to azer-cel treatment negatively correlated with differentiated CD4+ CCR7- cell dose (P=0.04).

Conclusions: Post-thaw product composition and effective cell dose are predictive for in vivo expansion potential, CAR-T-related adverse events and response to treatment with azer-cel. This is the first analysis of an allogeneic CD19 CAR T product composition to demonstrate that strategies intended to maximize stem central memory T-cell fraction (CCR7+) while limiting CD4+ CCR7- differentiated fraction may improve safety and efficacy of CAR T therapy.

Disclosures: Jacobson: BMS/Celgene: Consultancy; Novartis: Consultancy; Kite/Gilead: Consultancy, Research Funding; Pfizer: Research Funding; Abintus Bio: Consultancy; Miltenyi: Consultancy; Morphosys: Consultancy; Caribou Bio: Consultancy; ImmPACT Bio: Consultancy; Instil Bio: Consultancy; Ipsen: Consultancy; Epizyme: Consultancy; Bluebird Bio: Consultancy. Jayawardena: PrecisionBioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Yu: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Hallman: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Schmittling: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Cuneo: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Belle: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Sampey: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Cabral: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Derrick: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Tueller: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Olszewski: Adaptive Biotechnologies: Research Funding; Celldex: Research Funding; Acrotech Biopharma: Research Funding; Schrodinger: Consultancy; TG Therapeutics: Consultancy, Research Funding; Precision Bio: Research Funding; Genmab: Consultancy, Research Funding; Genentech: Research Funding. Maakaron: Gilead: Research Funding; CRISPR Therapeutics: Research Funding; Precision BioSciences: Research Funding; Scripps: Research Funding; Fate Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Reshef: Novartis: Honoraria; Atara Biotherapeutics: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Honoraria; Capstan Therapeutics: Consultancy; University Of Pennsylvania: Other: Data Safety Monitoring Board; J&J: Research Funding; Precision Biosciences: Research Funding; Takeda: Research Funding; Immatics: Research Funding; Shire: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; TScan: Consultancy; Bayer: Consultancy; Synthekine: Consultancy; Regeneron: Consultancy; MidaTech: Consultancy; Jasper: Consultancy. Stein: Amgen: Speakers Bureau. Deol: Janssen: Consultancy; Kite, a Gilead Company: Consultancy; Adicet: Consultancy. Jain: Ipsen: Honoraria; Mingsight: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Fate Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; TransThera Sciences: Research Funding; ADC Therapeutics: Research Funding; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; Servier Pharmaceuticals LLC: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; Incyte Corporation: Research Funding; CareDx: Honoraria; Pfizer: Research Funding; Beigene: Honoraria; Aprea Therapeutics: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; Takeda: Research Funding; Newave: Research Funding; Dialectic Therapeutics: Research Funding; Novalgen: Research Funding; Cellectis: Honoraria, Research Funding; Medisix: Research Funding; Pharmacyclics, Inc.: Consultancy, Honoraria, Other: Travel Support, Research Funding; Loxo Oncology: Research Funding. List: Precision BioSciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Servier: Other: grants and investigator-initiated trials; PeproMene Bio: Other: Steering committee; Autolus: Consultancy; Century Therapeutics: Consultancy; Adaptive: Consultancy; Pharmacyclics: Consultancy; Beigene: Consultancy; Acrotech: Consultancy; Jazz: Consultancy, Other: grants and investigator-initiated trials; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy, Other: grants and investigator-initiated trials; BMS/Celgene/Juno: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy.

*signifies non-member of ASH