Poseida Therapeutics (United States)

Abstract B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy has shown high initial response rates in relapsed/refractory multiple myeloma (RRMM), but most patients eventually relapse with progressive disease. Previous studies have identified a less differentiated, CD19-positive progenitor subpopulation of MM cells that contributes to resistance and poor survival. Furthermore, anti-CD19 CAR-T cells given after high-dose melphalan and stem cell transplantation have shown to improve patient survival and can eliminate MM progenitor cells that are resistant to BCMA-directed CAR-T cells. P-BCMACD19-ALLO1 is a fully allogeneic CAR-T therapy designed to target BCMA and CD19. Additionally, P-BCMACD19-ALLO1 is a T stem cell memory (TSCM)-rich product derived from healthy donor T cells using a nonviral, transposon-based system for transgene delivery, with knockout of TRBC1/2 and B2M to prevent graft-versus-host disease and reduce host T-cell mediated rejection, respectively. TSCM -rich CAR-Ts, including our BCMA-targeting allogeneic P-BCMA-ALLO1 CAR-T for RRMM (NCT04960579), have shown favorable efficacy and safety in the clinic. To develop P-BCMACD19-ALLO1, we constructed the BCMA CAR using two fully human, single-domain, heavy-chain variable domains (VHs) that independently bind BCMA and are joined together by a G4S linker in tandem. The tandem anti-BCMA VHs binds to all clinical escape mutants, including teclistamab-resistant R27P mutation. The anti-CD19 CAR binder comprises of a fully human VH against CD19. Both CARs are expressed from a single, multi-cistronic transgene that also contains an inducible Caspase-9 safety switch and a dihydrofolate reductase mutein. Herein, we show enhanced in vivo potency of P-BCMACD19-ALLO1against BCMA/CD19-double positive RPMI-8226 MM xenograft model using an optimized ICD combination that incorporates a novel co-stimulatory domain derived from the tumor necrosis factor receptor family member transmembrane activator and CAML interactor (TACI) in the CD19 CAR and the standard 4-1BB in the BCMA CAR. P-BCMACD19-ALLO1 demonstrates target-specific, in vitro cytotoxicity against tumor cells expressing BCMA, CD19, or both antigens but lacks activity against antigen-negative tumor cells. P-BCMACD19-ALLO1 also demonstrates potent, in vitro killing of tumor cells expressing R27P, P33Del, P33S and S30Del escape mutants. Lastly, P-BCMACD19-ALLO1 effectively eliminates primary bone marrow CD81+CD19+ progenitor cells as well as colony-forming cells derived from MM patient samples, suggesting that P-BCMACD19-ALLO1 may increase the depth and the durability of response. Taken together, our data underscore the therapeutic potential of P-BCMACD19-ALLO1 and support its application for treating RRMM to be further evaluated in clinical trials. Citation Format: Steven Wang, Iris Pang, Claudia Chang, Michelle Burrascano, Nick DeMarco, Danny Mendoza-Reyes, Sonia Reyes, Arturo Barcenas, Pastor Nieto, Jose Diaz, Garret Arauz, Chris Lynn, Tony Nguyen, Connor Reed, Mona Connerney, Quy Le, Julia Coronella, Devon J. Shedlock. Enhanced potency of BCMA/CD19 dual-targeting allogeneic CAR-T cells for relapsed/ refractory multiple myeloma with 4-1BB/TACI intracellular domains [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4811.

BackgroundMUC1 is a highly glycosylated protein that is expressed at the apical border of mucosal epithelium where it plays a protective role. MUC1 is comprised of an N-terminal subunit (MUC1N) tethered to a C-terminal subunit (MUC1C), forming a stable complex on the cell surface. A proteolytic ‘stump’ of MUC1C that may be aberrantly glycosylated is over-represented in cancer, making it an attractive therapeutic target. Here we report generation of allogeneic MUC1C-specific CAR T cells, P-MUC1C-ALLO1, that are designed to leverage the learnings of our P-BCMA-ALLO1 program. P-MUC1C-ALLO1 targets a MUC1C epitope and has the potential for efficacy against a wide range of solid tumors, without targeting normal epithelial cells.Methods mRNA-generated MUC1C CAR-T cells were evaluated for specificity and function by degranulation assay against various solid tumor and normal cells and cell lines. Autologous and allogeneic MUC1C CAR-T cells were produced using the piggyBac® DNA Modification System, a nonviral CAR-T manufacturing method that produces CAR-T products with an exceptionally high percentage of T stem cell memory (TSCM) cells. To produce allogeneic cells, multiplex editing of both TRBC and B2M was performed with the Cas-CLOVER™ Site-Specific Gene Editing System to reduce or eliminate GvHD and host versus graft alloreactivity, respectively. To determine in vivo antitumor efficacy of MUC1C CAR-T cells, we employed the MDA.MB.468 triple negative breast cancer model and the OVCAR3 disseminated ovarian cancer model.ResultsSpecific degranulation of transiently-expressing CAR+ T cells was observed against multiple tumor cells, with no observable activity against normal human primary cells. In assay of stable P-MUC1C-101 CAR-T cells, more than 95% expressed CAR, and were comprised of an exceptionally high-percentage of TSCM cells (CD45RA+CD62L+CD45RO-). In vitro, P-MUC1C-ALLO1 cells specifically proliferated, lysed, and secreted IFN-γ against MUC1C+ breast and ovarian tumor cell lines. In breast cancer in vivo xenograft model, both unedited (MUC1C CAR-T) and edited (P-MUC1C-ALLO1) MUC1C CAR-T eliminated established, triple negative MDA.MB.468 tumor cells to undetectable levels, demonstrating the efficacy of the MUC1C CAR-T and the robustness of the allogeneic platform. In the OVCAR3 xenograft model, intraperitoneally administered MUC1C CAR-T eliminated established tumor cells to levels below the limit of detection.ConclusionsP-MUC1C-ALLO1 is Poseida’s allogeneic CAR TSCM product that has a potential to treat multiple MUC1-expressing indications. P-MUC1C-ALLO1 displayed in vitro specificity for tumor vs normal cells, and in vivo efficacy against xenograft models of breast and ovarian cancer. We anticipate an IND filing and initiation of a Phase 1 clinical trial in 2021.

Acquired thrombotic thrombocytopenia purpura (TTP) is a life-threatening illness caused by autoantibodies that decrease the activity of ADAMTS13, the von Willebrand factor-cleaving protease. Despite efficacy of plasma exchange, mortality remains high and relapse is common. Improved therapies may come from understanding the diversity of pathogenic autoantibodies on a molecular or genetic level. Cloning comprehensive repertoires of patient autoantibodies can provide the necessary tools for studying immunobiology of disease and developing animal models. Anti-ADAMTS13 antibodies were cloned from four patients with acquired TTP using phage display and characterized with respect to genetic origin, inhibition of ADAMTS13 proteolytic activity, and epitope specificity. Anti-idiotypic antisera raised to a subset of autoantibodies enabled comparison of their relatedness to each other and to polyclonal immunoglobulin (Ig)G in patient plasma. Fifty-one unique antibodies were isolated comprising epitope specificities resembling the diversity found in circulating patient IgG. Antibodies directed both to the amino terminal domains and to those requiring the ADAMTS13 cysteine-rich/spacer region for binding inhibited proteolytic activity, while those solely targeting carboxy-terminal domains were noninhibitory. Anti-idiotypic antisera raised to a subset of antibody clones crossreacted with and reduced the inhibitory activity of polyclonal IgG from a set of unrelated patients. Anti-ADAMTS13 autoantibodies isolated by repertoire cloning display the diversity of epitope specificities found in patient plasma and provide tools for developing animal models of acquired TTP. Shared idiotypes of inhibitory clones with circulating IgG from multiple patients suggest common features of pathogenic autoantibodies that could be exploited for developing more targeted therapies.