Session: 704. Cellular Immunotherapies: Early Phase and Investigational Therapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Practice (Health Services and Quality), Clinical Research
Scientific Rationale: PRGN-3007 is built on Precigen’s UltraCAR-T platform and is engineered to simultaneously express a ROR1-specific chimeric antigen receptor (ROR1 CAR); membrane bound interleukin-15 (mbIL15) for enhanced in vivo expansion and persistence; a kill switch for improved safety profile; and a novel mechanism for the intrinsic blockade of programmed cell death protein 1 (PD-1) gene expression. Preclinical studies with PRGN-3007 UltraCAR-T cells showed significant reduction in PD-1 expression with increased ROR1 specific cytotoxicity and inflammatory cytokine production upon co-culture with ROR1+ PD-L1+ hematological and solid tumor cells. Furthermore, PRGN-3007 was selectively and effectively eliminated by the kill switch activator antibody treatment. In vivo, a single administration of PRGN-3007, effectively reduced tumor burden and significantly improved overall survival (p<0.05) of tumor bearing mice compared to Control ROR1 CAR-T in an aggressive xenograft model of mantle cell lymphoma. Blood analyses demonstrated sustained downregulation of PD-1 expression, rapid expansion, long-term persistence, and a predominant central memory phenotype of PRGN-3007 in tumor bearing mice. (Blood (2021) 138 (Supplement 1): 1694.)
Study Design: This is a first-in-human, Phase 1/1b dose escalation/dose expansion study to evaluate the safety and effectiveness of PRGN-3007 UltraCAR-T cells in patients with advanced ROR1-postive (ROR1+) hematologic (CLL, MCL, ALL, and DLBCL; Arm 1) and solid tumors (TNBC; Arm 2). Key inclusion criteria include absolute lymphocyte count ≥ 0.2k/µL, KPS > 70, adequate organ function, confirmed expression of ROR1 and: relapsed or refractory CLL; pathologically confirmed ALL B-cell precursor and measurable disease, pathologically confirmed MCL with overexpression of cyclin D1 or presence of t (11;14); pathologically confirmed DLBCL or high grade B-cell lymphoma including transformation from low grade lymphoma; or locally advanced unresectable or metastatic histologically confirmed TNBC with measurable disease as per RECIST 1.1.
Study subjects undergo leukapheresis followed by lymphodepletion with either fludarabine 30mg/m2 and cyclophosphamide 500mg/m2 for 3 days (Arm 1) or 60 mg/kg cyclophosphamide for 2 days (Arm 2). The study will enroll in 2 phases: an initial dose escalation phase followed by a dose expansion phase. Up to 4 dose levels are planned in dose escalation phase (Table 1), and the MTD will be determined separately in subjects in the hematologic arm and the solid tumor arm. The MTD for each arm will be expanded independently in the dose expansion phase of the study. All subjects will be followed for adverse events, CAR-T-related toxicities, disease response and PRGN-3007 cell expansion and persistence. In addition, the mechanisms of safety and effectiveness of PRGN-3007 cells will be evaluated with correlative assays of specific immune response pathways.
Disclosures: Pinilla Ibarz: AstraZeneca: Consultancy; SecuraBio: Research Funding; AbbVie: Consultancy; Pharmacyclics: Consultancy; Janssen Pharmaceuticals: Consultancy. Lankford: Precigen: Current Employment, Current equity holder in publicly-traded company. Sabzevari: Precigen: Current Employment, Current equity holder in publicly-traded company; Kinnate Biopharma: Membership on an entity's Board of Directors or advisory committees. 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. Chavez: GenMab: Consultancy; Janssen: Research Funding; MorphoSys/Incyte: Speakers Bureau; Merck: Research Funding; Abbvie: Consultancy; Epizyme: Honoraria, Speakers Bureau; ADC Therapeutics: Research Funding; Kite Pharma: Consultancy; Adicet: Consultancy; Beigene: Honoraria; TG Therapeutics: Honoraria; Astrazeneca: Research Funding, Speakers Bureau. Shah: Precigen: Current Employment.
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