MHC class II targeted immunotherapy in the treatment of pancreatic cancer

Introduction : Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumor types, claiming approximately 50,000 lives per year in the United States and carrying a 5-year overall survival rate of only 13%. While immunotherapy has revolutionized therapy for certain cancer types, this has not been the case for PDAC, where there have been zero immunotherapy approvals. This is attributed to a variety of factors related to the PDAC tumor microenvironment (TME) including its dense desmoplastic stroma with high interstitial pressure and a prevalence of immunosuppressive cell types. In addition, genetic characteristics like microsatellite instability (MSI) and high mutational burden, which predict responsiveness to immune checkpoint inhibitors (ICIs), are absent or low in PDAC compared to more responsive tumor types. This suggests that effective anti-tumor immune responses depend on tumor-derived immunogenic signals, leading us to explore new strategies to stimulate immunity against PDAC-associated antigens. We developed a Major Histocompatibility Complex class II (MHCII) targeted approach to direct the immune system against PDAC associated antigens. MHCII is a major antigen presentation complex that directly educates CD4+ helper T cells, and studies have shown that MHCII-CD4 signaling is essential for effective anti-cancer immunity. Specifically, we developed a recombinant high affinity MHCII engager that is conjugated to mesothelin (MSLN), which is overexpressed in a high percentage of PDAC but not the normal pancreas. Methods: To evaluate the preclinical efficacy of our MHCII targeted MSLN therapy (LTI-002), we injected KPC mouse PDAC cells orthotopically in syngeneic C57BL/6 mice. Tumor burden was measured at a predetermined endpoint or by survival analysis. Pharmacodynamic markers of immune response including anti-MSLN specific IgGs and antigen-specific T cell recall were also evaluated. Results: This approach induced a polyclonal humoral response and antigen specific T cell response against mouse and human MSLN candidates. This led to a significant reduction in the size of orthotopic PDAC tumors and significantly improved animal survival. Anti-tumor responses were detected in therapeutic as well as prophylactic experiments and further demonstrated in the de novo KPF mouse PDAC model and in a model of PDAC metastasis. We observed synergy in combination with PDAC standard of care agents like gemcitabine, RAS(ON) inhibitors, and anti-PD1 immunotherapy. As a direct MHCII engager, LTI-002 induced internalization of MSLN into early endosomes where it was processed and loaded onto new MHCII molecules for presentation to CD4+ T cells. LTI-002 target engagement was independent of MHCII polymorphisms, which is an advantage given the diversity of HLA alleles found in different human populations. Conclusions: This study demonstrates the therapeutic potential of targeting MHCII to stimulate anti-PDAC immunity.