Safety and Activity of PolyPEPI1018 Combined with Maintenance Therapy in Metastatic Colorectal Cancer: an Open-Label, Multicenter, Phase Ib 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.

Associating resistance to immune checkpoint inhibitors with immunological escape in colorectal cancer

“…Ultimately, there were no serious side effects from the vaccine, five patients got a single dose of PolyPEPI1018 and six patients got up to three doses every 12 weeks. Three patients progressed, five patients were stable, and three patients had partial tumor remission, two of whom had tumors that were small enough to undergo surgery (30). This is an advancement for MSS-CRC.…”

Colorectal Cancer Stem Cells and Targeted Agents

“…For example, B16F10 CD133+/CD44+CSCs vaccine can effectively inhibit melanoma growth in mice and reduce the CSC population within tumors [ 97 ]. Although no cancer stem cell vaccine has entered clinical trials at this time, the demonstrated efficacy of a vaccine targeting metastatic CRC is reassuring and raises hope [ 98 ].…”

Immunological Assessment of Recent Immunotherapy for Colorectal Cancer

“…Another recent phase IIb clinical study was based on the multi-peptide vaccine PolyPEPI1018 (clinical trial identi er: NCT03391232) to induce T-cell responses against cancer testis antigens expressed in colorectal tumors [127]. The extended period of median PFS was 12.5 months in multiple vaccination recipients compared with a single dose [127].…”

“…Another recent phase IIb clinical study was based on the multi-peptide vaccine PolyPEPI1018 (clinical trial identi er: NCT03391232) to induce T-cell responses against cancer testis antigens expressed in colorectal tumors [127]. The extended period of median PFS was 12.5 months in multiple vaccination recipients compared with a single dose [127]. Using in vitro stimulated ELISpot assay that assessed the induced CD8 + and CD4 + T-cell response and hence recruitment of cytotoxic tumor-in ltrating lymphocytes to tumor region converting "cold" tumor into "hot" tumor (Table 2) [127].…”