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Abstract Background Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. Methods We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates. Results Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval [CI], 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients. Conclusions GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.

Axon guidance molecules are frequently altered in pancreatic ductal adenocarcinoma (PDA) and influence PDA progression. However, the molecular mechanism remained unclear. Using genetically engineered mouse models to examine semaphorin 3D (SEMA3D), we identified a dual role for tumor- and nerve-derived SEMA3D in the malignant transformation of pancreatic epithelial cells and invasive PDA development. Pancreatic-specific knockout of the SEMA3D gene from the KRAS G12D and TP53 R172H mutation knock-in, PDX1-Cre(KPC) mouse model demonstrated delayed tumor initiation, prolonged survival, absence of metastasis, and reduced M2 macrophage expression. Mechanistically, tumor- and nerve-derived SEMA3D indirectly reprograms macrophages through KRAS MUT -dependent ARF6 signaling in PDA cells, resulting in increased lactate production, which is sensed by GPCR132 on macrophages to stimulate protumorigenic M2 polarization. Multiplex immunohistochemistry demonstrated increased M2-polarized macrophages proximal to nerves in SEMA3D-expressing human PDA tissue. This study suggests that altered SEMA3D expression leads to an acquisition of cancer-promoting functions, and nerve-derived SEMA3D is "hijacked" by PDA cells to support growth and metastasis in a KRAS MUT -dependent manner.