Safety and activity of PolyPEPI1018 combined with maintenance therapy in metastatic colorectal cancer: an open-label, multicenter, phase 1b study

Abstract Purpose: Although chemotherapy is standard-of-care for metastatic colorectal cancer (mCRC), immunotherapy has no role in microsatellite stable (MSS) mCRC, a "cold" tumor. PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine derived from 7 tumor-associated antigens (TAAs) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in MSS mCRC patients. Experimental Design: 11 patients with MSS mCRC received PolyPEPI1018 and Montanide ISA51VG adjuvant subcutaneously, combined with fluoropyrimidine/biologic following first-line induction with chemotherapy and a biologic (NCT03391232). In Part A of the study five patients received a single dose, in Part B six patients received up to three doses of PolyPEPI1018 every 12 weeks. The primary objective was safety, secondary objectives were preliminary efficacy, immunogenicity at peripheral and tumor-level, and immune correlates. Results: PolyPEPI1018 vaccination was safe and well tolerated. No vaccine-related serious adverse event occurred. 80% of patients had CD8+ T-cell responses against {greater than or equal to}3 TAAs. Increased density of tumor-infiltrating lymphocytes were detected post-treatment for 3 of 4 patients' liver biopsies, combined with increased expression of immune-related gene-signatures. Three patients had objective response according to RECISTv1.1, and two patients qualified for curative surgery. Longer median progression-free survival for patients receiving multiple doses compared with a single dose (12.5 vs 4.6 months; p=0.017) suggested a dose-efficacy correlation. The host HLA genotype predicted multi-antigen-specific T-cell responses (p=0.01) indicative of clinical outcome. Conclusions: PolyPEPI1018 added to maintenance chemotherapy for patients with unresectable, MSS mCRC was safe and associated with specific immune responses and antitumor activity warranting further confirmation in a randomized, controlled setting.