Safety and immunologic impact of neoadjuvant/adjuvant GVAX, cyclophosphamide, pembrolizumab, and anti-CSF1R agent IMC-CS4 in pancreatic adenocarcinoma.

BACKGROUND: We previously reported that an increased M1/M2 ratio and decreased PDL1+ M2- like tumor-associated macrophages (TAM) are associated with longer survival in patients with pancreatic adenocarcinoma (PDA). Targeting M2-like macrophages may improve patients' outcomes. In this pilot study, we hypothesized targeting M2-like macrophages, regulated by the colony stimulating factor-1 (CSF1) pathway, would be safe and induce an intratumoral immune response in patients with PDA.

METHODS: We tested perioperative combination immunotherapy (CI) with GM-CSF-secreting allogenic pancreatic tumor cell vaccine (GVAX)/cyclophosphamide (CY), pembrolizumab (Pem), and CSF1 receptor blockade (IMC-CS4) in patients with PDA. Patients received two neoadjuvant cycles of CI followed by surgery and four adjuvant cycles of CI. Subsequently, they received a booster Pem every 3 weeks and GVAX/CY every 6 months, for up to one year. The co-primary endpoints were safety and immune response in paired biopsies.

RESULTS: Nine patients were enrolled and treated in this study. We observed two immune related grade 3/4 AEs (diarrhea and rash). Comparison of paired biopsies showed five of eight evaluable patients met the immunologic endpoint with >80% increase in CD8+ T cells. The increase was at least 1.8 times the baseline median absolute deviation.

CONCLUSION: CI has a manageable safety profile and leads to increased intratumoral cytotoxic effector T cells.

CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT03153410, identifier NCT03153410.