Abstract 46P
Background
Most solid tumors are of epithelial origin and express Mucin 1 (MUC1), a heterodimer of MUC1-N and the oncogenic subunit MUC1-C. Many drugs targeting MUC1 in clinical trials have been primarily directed against MUC1-N. Since MUC1-C is present broadly in tumor due to loss of cell polarity, exposure via hypoglycosylation and MUC1-N shedding, it may represent a more tumor-selective target than MUC1-N. P-MUC1C-ALLO1 is an allogeneic CAR-T targeting MUC1-C and is manufactured using transposon-based integration (piggyBac® DNA Delivery System) and the Cas-CLOVER™ Gene Editing System to knockout the TCR and MHC class I proteins resulting in an enriched T stem cell memory product. Thus, P-MUC1C-ALLO1 addresses multiple common solid tumor indications.
Methods
MUC1-C epitope expression was investigated by IHC using the scFv binder for P-MUC1C-ALLO1 CAR in epithelial tumor and normal frozen tissue arrays. Pre-clinical efficacy of P-MUC1C-ALLO1 was tested in xenograft models for triple-negative breast (TNBC) and ovarian cancers. Clinical safety has been evaluated in three patients in a phase I trial (NCT05239143).
Results
MUC1-C epitope was positive in multiple tumor samples. While tumor expression was relatively nonpolarized, normal tissue expression was restricted to the apical surface. P-MUC1C-ALLO1 demonstrated robust infiltration and activity in TNBC and ovarian cancer xenografts, with >90% of tumor mass comprised of CAR-Ts at day 10, and 100% tumor elimination at 2 weeks. In the phase I trial, 4 pts (esophageal, colorectal, breast, and pancreatic carcinomas) have been infused either at 0.75x106 (pts 1-3) or 2x106 cells/kg (pt 4). No P-MUC1C-ALLO1 related toxicities were observed. Early efficacy was seen at the low dose with one partial response in pt 3 (HR+, Her2- Breast cancer).
Conclusions
MUC1-C epitope is highly expressed across common epithelial cancers and is apically restricted in normal tissues. Potent anti-tumor activity is seen in preclinical models. In early phase I experience, P-MUC1C-ALLO1 is safe and tolerable with an early signal of efficacy at a low starting dose. P-MUC1C-ALLO1 phase I trial enrollment is on-going.
Clinical trial identification
NCT05239143.
Legal entity responsible for the study
Poseida Therapeutics, Inc.
Funding
Poseida Therapeutics, Inc.
Disclosure
D. Oh: Financial Interests, Personal, Invited Speaker, Licensing fees relating to a patent on the use of T cell receptor sequencing as a predictive marker of immune-related adverse events with immunotherapy: Regents of the University of California; Financial Interests, Personal and Institutional, Invited Speaker, Research support: Merck Sharp and Dohme, PACT Pharma, Poseida Therapeutics, TCR2 Therapeutics, Roche/Genentech, Nutcracker Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Proprietary materials for laboratory experimentation: Nutcracker Therapeutics, 3T Biosciences. J. Henry: Financial Interests, Personal, Full or part-time Employment, Associate Director/Oncologist: Sarah Cannon Research Institute; Financial Interests, Personal, Stocks/Shares: HCA; Financial Interests, Institutional, Invited Speaker: Abbiscko Therapeutics, ABl Bio, Accutar biotech ADC therapeutics, Agenus, Aileron Therapeutics, Amgen inc, Artios, AstraZeneca, Bicycle Therapeutics, BioAlta, BioInvent Pharma, Biosplice Therapeutics, Black Diamond Therapeutics, Boehringer, Ingelheim, Cyteir, Daiichi Sankyo, Eli Lilly, Epizyme, Erasca, Exelixis, FujiFilm, GSK, Hutchison MediPharma, ICON plc, IGM Biosciences, Immunogen, Jacobio Pharmaceuticals, Jounce Pharma, Jubilant therapeutics, Loxo Oncology, Merck& CO, Metabomed, Molecular templates, Navire Pharma, Nikang pharmaceuticals, Oncorus, Prelude therapeutics, Poseida, PureTech, Pyramid, Rascal Therapeutics, Regeneron, Relay Therapeutics, Rgenix inc, Ribon therapeutics, Sapience, Sarah Cannon Development Innovations, Sarah Cannon Research Institute, Seagen, Simcha Therapeutics, Siranomics, Stingthera, Synthorx inc, Takeda pharmaceuticals, Tallac therapeutics, Tarveda, Teneothree, Tesaro, Turning Point Pharma, Xencor. J.C. Baranda: Financial Interests, Institutional, Other, Consultant: Sanofi; Financial Interests, Personal, Stocks/Shares: Aprea, Moderna, Zyme, Merus, Hutchmed; Financial Interests, Institutional, Invited Speaker: Astellas, Nektar, Sanofi, Takeda, Pfizer, SQZ, Synermore, Changchun Intellicrown, Genome and Company, Sumitomo Pharma, Xencor. E.E. Dumbrava: Financial Interests, Personal and Institutional, Research Grant: Bayer Healthcare Pharmaceuticals Inc, Immunocore Ltd, Amgen, NCI, Aileron Therapeutics, Compugen Ltd, TRACON Pharmaceuticals Inc, Unum Therapeutics, Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira, Seagen Inc, Mereo BioPharma 5 Inc, Sanofi, Astex Therapetics ; Financial Interests, Personal, Advisory Board: BOLT Therapeutics, Mersana; Financial Interests, Personal, Advisory Role: Catamaran Bio. E. Cohen: Financial Interests, Personal, Other, Consulting: Axelia, Cel Sci, Eisai, Hoopika, ImmunoSensor, Istari, Janssen, Kahr Medical, Mana Therapeutics, Merck, Mirati, MSD, Nectin Tx, Pangea Therapeutics, Roche; Financial Interests, Personal, Other, DSMB: Ayala, Kura; Financial Interests, Personal, Stocks/Shares: Kinnate Biophama, Primmune Therapeutics. J.D. Eskew: Financial Interests, Personal, Full or part-time Employment: Poseida Therapeutics; Financial Interests, Personal, Stocks/Shares: Poseida Therapeutics. R. Belani: Financial Interests, Personal, Stocks/Shares: Poseida, Amgen; Financial Interests, Personal, Full or part-time Employment: Poseida. J. McCaigue, H. Namini, C. Martin, A. Murphy: Financial Interests, Personal, Full or part-time Employment: Poseida; Financial Interests, Personal, Stocks/Shares: Poseida. E. Ostertag: Financial Interests, Personal, Member of the Board of Directors: Poseida Therapeutics; Financial Interests, Personal, Stocks/Shares: Poseida Therapeutics; Financial Interests, Personal, Full or part-time Employment: Poseida Therapeutics. J. Coronella, D. Shedlock: Financial Interests, Personal, Full or part-time Employment: Poseida Therapeutic; Financial Interests, Personal, Stocks/Shares: Poseida Therapeutics. I.I. Rodriguez Rivera: Financial Interests, Institutional, Full or part-time Employment: Next Oncology; Non-Financial Interests, Personal, Principal Investigator: Omega Therapeutics, Poseida Therapeutics, Werewolf Therapeutics, Merck KGaA.