Intra-tumoral CD40 antibody with irreversible electroporation (IRE) in locally advanced pancreas cancer.

Abstract

TPS787 Background: Irreversible electroporation (IRE) is a form of non-thermal tumor ablation that is currently in clinical use for selected patients with locally advanced pancreatic cancer (LAPC). Preclinical and clinical studies have suggested that IRE generates an in situ vaccination effect by releasing tumor neoantigens in the setting of inflammation. Our published data from syngeneic, orthotopic mouse models demonstrate that combination of IRE with local CD40 agonism induces systemic anti-tumor immune effects, including neoantigen-specific T-cell responses and inhibition of liver metastases (1). Mitazalimab, a second-generation CD40 agonistic IgG1 mAb, has demonstrated promising clinical antitumor activity when delivered systemically in combination with modified FOLFIRINOX in metastatic pancreatic cancer (2). Methods: This clinical trial (NCT06205849) is a phase I dose-escalation study of an agonistic CD40 antibody (mitazalimab) injected intratumorally at the time of surgical IRE in patients with LAPC who have not demonstrated distant disease progression after a minimum of 4 months of optimal standard of care (SOC) chemotherapy (modified FOLFIRINOX). The doses investigated are 25, 75 (starting dose), and 200 µg/kg, in an interval 3+3 design, with a maximum of 18 subjects. The primary endpoints are the rates of dose limiting toxicities (DLTs) and treatment-emergent adverse events (AEs). The secondary endpoints are progression-free survival (PFS) and overall survival (OS). At a liberal alpha of 25%, appropriate for this proof-of-concept early phase study, we have 80% power to detect an improvement in PFS from 12 months (based on prior studies of IRE alone) to 18 months, with an expected 16 evaluable subjects and an anticipated 11 observed events, using a one-sided log-rank test. Candidate neoantigens will be identified by profiling nucleic acids derived from tumor biopsies obtained intraoperatively prior to IRE using our Identification-Prioritization-Validation (IPV) bioinformatic pipeline (3). Blood samples will be collected pre-operatively and 12-weeks post-operatively to evaluate for evidence of neoantigen-specific T-cell reactivity and other neoantigen-independent analyses of immune response. We have enrolled two patients since the study opened in September 2024. 1. J. Shankara Narayanan et al., JITC 2023. 2. J. Van Laethem et al., Lancet Oncol 2024. 3. A. Miller et al., Sci Transl Med. 2024. Clinical trial information: NCT06205849 .