Abstract 2376: Mitazalimab, a potent CD40 agonist in combination with FOLFIRINOX demonstrates changes consistent with increased immune activation in TME and peripheral blood in a preclinical pancreatic cancer tumor model

Abstract Mitazalimab is a human CD40 FcγR-conditional agonistic IgG1 antibody developed for cancer immunotherapy. Immune-excluded tumors, such as pancreatic ductal adenocarcinoma (PDAC), are defined by low infiltration of immune cells. In PDAC, effector CD8+ T cells are excluded from the tumor by its desmoplastic stroma which surrounds cancer cell islets and hosts immunosuppressive macrophages. CD40 is expressed on key myeloid cell populations and targeting this receptor has a two-fold mode of action. First, mitazalimab activates macrophages, skewing them towards a tumoricidal phenotype that can potentially reverse the suppressive tumor microenvironment found in PDAC and sensitizes the tumor for chemotherapy by stromal degradation. Second, mitazalimab activates antigen-presenting cells, resulting in priming and expansion of tumor-specific T cells with the potential to generate an effective immune response that could provide immunological memory resulting in long term benefits to patients. Mitazalimab is currently being investigated in a phase 2 study in patients with metastatic PDAC (OPTIMIZE-1) in combination with modified FOLFIRINOX (NCT04888312). The treatment starts with a dose of mitazalimab administered one week prior to chemotherapy in the first cycle to leverage the mode of action and increase the efficacy of the combination therapy. Interim results of the study demonstrated encouraging anti-tumor activity with good durability of responses. To study the changes induced by mitazalimab and FOLFIRINOX in the tumor microenvironment, we evaluated the combination in human CD40 transgenic mice using the KPCY pancreatic tumor model. Tumor, tumor draining lymph nodes, blood and spleen were analyzed for changes in the immune compartment using multiplex assays at different time points. The results showed distinct immunophenotypical changes induced by mitazalimab, FOLFIRINOX and the combination. The combination of mitazalimab and FOLFIRINOX resulted in an increased tumoricidal immune profile, including a marked increase in effector CD8+ T cells compared to the individual therapies. Overall, these preclinical data support the chosen dosing regimen of mitazalimab and modified FOLFIRINOX in the OPTIMIZE-1study and underline the synergistic potential of this combination for an improved antitumor response. Citation Format: Karin Enell Smith, David Gomez Jimenez, Mia Thagesson, Anneli Nilsson, Yago Pico de Coaña, Sumeet Ambarkhane, Peter Ellmark. Mitazalimab, a potent CD40 agonist in combination with FOLFIRINOX demonstrates changes consistent with increased immune activation in TME and peripheral blood in a preclinical pancreatic cancer tumor model abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2376.