Neoadjuvant CD40 agonism remodels the tumor immune microenvironment in locally advanced esophageal/gastroesophageal junction cancer [scRNA-seq]

Sotigalimab (sotiga) is an agonistic anti-CD40 monoclonal antibody that can modulate anti-tumor immune responses. In a clinical trial of sotiga combined with neoadjuvant chemoradiation (CRT) in locally advanced esophageal/gastroesophageal junction cancer, treatment induced pathologic complete responses in 38% of patients. Using high-dimensional single cell techniques, we found that sotiga dramatically re-modeled both peripheral immune responses and the tumor microenvironment (TME), increasing components of antigen processing and presentation and altering metabolic pathways in myeloid cells. Concomitant with myeloid cell alterations, sotiga primed new T cell clonotypes, increased T cells with enhanced cytotoxic activity, and decreased the frequency of Tregs in the TME. Clinical responses were associated with both baseline and treatment-induced T cell states. These findings indicate that sotiga induces antigen presentation leading to enhanced T cell activation and clinical response, and that the immune composition of the TME at baseline is important in conferring sensitivity to this treatment approach. Tumor samples were obtained from patients pre- and on-treatment as part of a phase II clinical trial clinical trial (NCT03165994). Treatment regimen was carboplatin (AUC 2)/paclitaxel (50 mg/m2) weekly for 5 weeks and concurrent radiation 5040 cGy in 28 fractions, and up to 4 doses of sotigalimab 0.3mg/kg IV between weeks 1-10, followed by Ivor-Lewis esophagectomy. Tumor biopsies were performed prior to the initiation of treatment (pre-treatment) and 1-2 weeks after the first dose of sotiga prior to chemoradiation (post-treatment); when available, surgical resections were also collected for correlative analysis.