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 (TAA) frequently expressed in mCRC. This study assessed PolyPEPI1018 combined with first-line maintenance therapy in patients with MSS mCRC.

Patients and methods: Eleven 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, 5 patients received a single dose; in Part B, 6 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. Eighty percent of patients had CD8+ T-cell responses against ≥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 2 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.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.

Antitumor activity. A, Maximum changes from baseline in sum of target lesion size. B, Spider plot showing the changes of the target lesion sizes at each radiologic assessment (6-weekly). Each data point was compared with the lesion size measured at baseline. Dotted lines indicate patients receiving a single dose. CT scans and individual target lesion size changes for Patient 02–0004 (C), Patient 01–0004 (D), and Patient 01–0007 (E). Dotted lines denote post-study data for Patient 01–0007. Triangles indicate vaccination dates. Different gray shades on the line graphs and different colored arrows on the scans indicate different target lesions of the patients. *, This patient was considered with PD due to clinical progression by the investigator.

Figure 2.

Durability of responses (post hoc analysis). A, Swimmer plot analysis for the individual disease courses prior-, during-, and post-study. B, Kaplan–Meier curve for the PFS of single- and multiple-dose groups. One patient (Patient 01–0008) from Part B who progressed after one dose and left the trial was included in the single dose group. Number of patients at risk is shown below the Kaplan–Meier curve. The Kaplan–Meier analysis contains censored data for curative surgery, RT, and LFU. PFS was calculated as the time from the date of initiating maintenance therapy to the date of first progression or censored. Post-study, the patients continued on maintenance treatment; for the 3 patients with curative surgery/RT, therapy was discontinued after surgery/RT. LFU, lost to follow-up; RT, radiotherapy.

Figure 3.

Colorectal cancer–specific immune responses induced by PolyPEPI1018 at peripheral and tumor level indicate treatment benefit. A, The breadth of TAA-specific CD8+ T-cell responses and magnitude of CD4+ T-cell responses in each patient measured by IVS ELISpot. Post-vaccination (Po) results are the maximum responses measured for each subject during the study. CD8 T-cell responses were measured using the individual 9-mer test peptides listed in Supplementary Table S1, and summed for obtaining TAA-specific responses. CD4 T-cell responses were measured with the pooled 30-mer peptides. B, Number of responsive vaccine TAAs plotted by patient (n = 10). Dark gray bars: Pre-only: No change or <2-fold increase in responses compared with pre-vaccination; mid gray bars: response boosted compared with pre-vaccination (at least 2-fold increase by IVS ELISpot); light gray: de novo induced vaccine-specific immune responses (no pre-vaccination response measured). C, Magnitude of PolyPEPI1018 vaccine-specific CD8+ and CD4+ T-cell responses detected at baseline and after multiple doses. D, T-cell (TIL) infiltration to the CT and IM area of the tumors post-vaccination assessed by HalioDx's Immunoscore CR TL assay. Changes in TIL density were calculated from IHC data obtained for pre/post-vaccination biopsy pairs; pre: baseline sample (except for Patient 01–0002, it was week 12 sample); Post: tumor biopsy at week 12 (for Patients 02–0002 and 02–0004) or week 38 (Patients 01–0002 and 01–0007). E, Whisker plot of upregulated gene-expression signatures upon treatment with PolyPEPI1018 for responder (R) tumors (Patients 02–0004, 01–0002, and 01–0007) and a nonresponder (NR) tumor (Patient 02–0002) assessed by NanoString's PanCancer gene-expression panel. Each dot represents the fold change of a gene in a sample. Boxes on the plot represents the quartiles (1 to 3). CD8+ effector T-cell gene signature: [CD8A molecule (CD8A), CD8B molecule (CD8B), eomesodermin (EOMES), granzyme A (GZMA), granzyme B (GZMB), IFNγ (IFNG), and perforin 1 (PRF1)]; IFNγ gene signature: [indoleamine 2,3-dioxygenase 1 (IDO1), C-X-C motif chemokine ligand (CXCL) 9 and 10, MHC class II DR α (HLA-DRA), signal transducer and activator of transcription 1 (STAT1) and IFNG] and PD-L1 and PD-L2 gene signatures. F, Impact of TAA-specific CD8+ T-cell responses boosted by the vaccine (measured by IVS ELISpot) on treatment benefit; DCB, durable clinical benefit = patients with objective tumor response (PR) and/or stabilized disease (SD) for at least 50 weeks on maintenance treatment; Others: patients with no DCB. ΔSFU, background corrected spot-forming units; #, number. ND, not detected; ns., not significant. Error bars represent SEM.