PBCAR19B, an Immune Evading Allogeneic CAR T Stealth Cell, Demonstrates Potent Anti-Tumor Responses and Prolonged B Cell Depletion Supporting Sustained Immune Evasion in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma (NHL)

Background: The efficacy of CAR T cell products has been limited by host immune rejection. PBCAR19B or “Stealth Cell” is a of cluster of differentiation (CD)19-directed allogeneic CAR T-cell therapy designed to evade immune rejection in order to extend target engagement and improve clinical efficacy. PBCAR19B is derived from healthy donor T cells in which a stealth construct is inserted into the T cell receptor alpha constant (TRAC) gene locus via a TRAC-specific ARCUS nuclease. In addition to the anti-CD19 CAR gene, the stealth construct carries a microRNA that suppresses expression of beta-2 microglobulin (B2M), a component of Class 1 major histocompatibility complex (MHC) molecules found on the cell surface. Reducing or knocking down Class 1 expression on allogeneic CAR T cells has been shown to reduce CAR T cell killing by cytotoxic T cells. The stealth construct also carries a HLA-E gene intended to prevent rejection of CAR T cells by NK cells that can be stimulated as a result of reduced MHC expression on the cell surface. Together, these key features position PBCAR19B as a potential off-the-shelf-treatment with improved persistence in CD19-related indications. Methods: PBCAR19B was administered as a single infusion to adult subjects with measurable CD19+ R/R NHL. Prior hematopoietic cell transplant or treatment with a CD19-directed autologous CAR T therapy was permitted. Two lymphodepletion (LD) regimens were tested, including standard (sLD), fludarabine 30 mg/m2/day × 3 days + cyclophosphamide 500 mg/m2/day × 3 days, and an augmented cyclophosphamide (Aug-Cy LD) regimen where 750 mg/m2/day × 3 days with standard fludarabine. Following a two-day washout, PBCAR19B was infused as a flat dose of 270 million (DL1) or 540 million cells (DL2) CAR T cells. Response was evaluated using Lugano 2016 criteria. Immune populations and CAR T cell kinetics were enumerated by flow cytometry and ddPCR, respectively. Pharmacodynamic responses were assessed by multiplex cytokine assays. Results: Thirteen subjects with aggressive and advanced disease were treated. Median age was 67 years with a mean of 3.6 lines (maximum 9) of prior treatment. Three subjects were treated at DL1 following sLD with one partial response (PR) at Day 28 despite minimal CAR T expansion. Ten additional subjects were treated at DL2, including three subjects who received sLD. Two sLD subjects responded (1CR [DLBCL], 1PR [DLBCL]) with 1 PD [HGBCL], with the CR sustained for 6 months. Additional subjects received DL2 following Aug-Cy LD including two with mantle cell lymphomas (MCL) and five with DLBCL. Four of five DLBCL subjects (80%) achieved CR of 3-12+ months duration with 60% MRD- at day 28; one MCL subject achieved a PR. PBCAR19B showed a highly favorable safety profile with no ≥ Grade 3 allogeneic CAR T-related AEs. Interestingly, profound and prolonged B cell depletion was observed at DL2, sustained beyond 90 days. Consistent with the immune evasion design, T-cell and NK cell recovery were significantly delayed relative to other CAR T programs. Conclusions: PBCAR19B demonstrated promising efficacy (ORR 70%) with a high frequency of CR in DLBCL, prolonged CD19+ B cell depletion, and a favorable safety profile. Delayed T cell and NK cell recovery supports mitigation of CAR T host rejection by the immune cloaking construct.

Gergis:Biontech: Current equity holder in publicly-traded company; VOR: Consultancy; Moderna: Current equity holder in publicly-traded company; Iovance: Current equity holder in publicly-traded company; Kite: Other: Travel Support, Speakers Bureau; Incyte: Other: Travel Support, Speakers Bureau; Astellas: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; Autolus: Consultancy. Martin:Precision BioSciences, Inc.: Current Employment. Vogel:Precision BioSciences, Inc.: Current Employment. Smith:Precision BioSciences, Inc.: Current Employment. Reshef:Precision Biosciences: Research Funding. List:Precision BioSciences, Inc.: Current Employment. Herrera:Karyopharm: Consultancy; Regeneron: Consultancy; AbbVie: Consultancy; KiTE Pharma: Research Funding; Genmab: Consultancy; Adicet Bio: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Gilead Sciences: Research Funding; Allogene Therapeutics: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy, Research Funding; Caribou Biosciences: Consultancy; Roche/Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy. Jain:Kite/Gilead: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Incyte: Research Funding; Loxo: Research Funding.