Arginase-1 targeting peptide vaccine in patients with metastatic solid tumors - A phase I trial

Abstract

Background: Arginase-1-producing cells inhibit T cell-mediated anti-tumor responses by reducing L-arginine levels in the tumor microenvironment. T cell-facilitated elimination of arginase-1-expressing cells could potentially restore L-arginine levels and improve anti-tumor responses. The activation of arginase-1-specific T cells may convert the immunosuppressive tumor microenvironment and induce or strengthen local Th1 inflammation. In the current clinical study, we examined the safety and immunogenicity of arginase-1-based peptide vaccination.

Methods: In this clinical phase I trial, ten patients with treatment-refractory progressive solid tumors were treated. The patients received an arginase-1 peptide vaccine comprising three 20-mer peptides from the ARG1 immunological "hot spot" region in combination with the adjuvant Montanide ISA-51. The vaccines were administered subcutaneously every third week (maximum 16 vaccines). The primary endpoint was to evaluate safety assessed by Common Terminology Criteria for Adverse Events 4.0 and laboratory monitoring. Vaccine-specific immune responses were evaluated using enzyme-linked immune absorbent spot assays and intracellular cytokine staining on peripheral blood mononuclear cells. Clinical responses were evaluated using Response Evaluation Criteria in Solid Tumors 1.1.

Results: The vaccination was feasible, and no vaccine-related grade 3-4 adverse events were registered. Nine (90%) of ten patients exhibited peptide-specific immune responses in peripheral blood mononuclear cells. Six (86%) of the seven evaluable patients developed a reactive T cell response against at least one of the ARG1 peptides during treatment. A phenotypic classification revealed that arginase-1 vaccine-specific T cells were both CD4+ T cells and CD8+ T cells. Two (20%) of ten patients obtained stable disease for respectively four- and seven months on vaccination treatment.

Conclusion: The peptide vaccine against arginase-1 was safe. Nine (90%) of ten patients had measurable peptide-specific responses in the periphery blood, and two (20%) of ten patients attained stable disease on protocol treatment.

Clinical trial registration: https://ichgcp.net/clinical-trials-registry/NCT03689192, identifier NCT03689192.

Keywords: arginase-1; first-in-human; peptide; solid tumors; vaccination.

Conflict of interest statement

MA has various patent applications in relation to the therapeutic uses of ARG1 peptides. The patents are allocated to the company IO Biotech. MA is a founder, advisor, and shareholder for IO Biotech. EM, AP, and EE are employees at IO Biotech. IS has lectured for or had advisory board relationships with MSD, Sanofi Aventis, BMS, Pierre Fabre, Novartis, TILT Biotherapeutics, IO Biotech, and Novo Nordisk. IS has received research grants from Lytix biopharma, IO Biotech, BMS, Adaptimmune, and TILT Biotherapeutics. IS is a co-founder and shareholder for the company IO Biotech. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Lorentzen, Martinenaite, Kjeldsen, Holmstroem, Mørk, Pedersen, Ehrnrooth, Andersen and Svane.

Figures

Figure 1

Consort diagram. Twenty patients with metastatic solid tumors were assessed for eligibility. Thirteen patients were enrolled and received the study treatment. Three patients received

Figure 2

Heatmaps of detected specific arginase-1 (ARG1) responses in peripheral blood mononuclear cells (PBMCs) at baseline and on treatment as measured by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay (n=10). Background has been subtracted. *Indicates positive responses based on Distribution-free Resampling (DFR) method.

Figure 3

CD4+ and CD8+ arginase-1 (ARG1) vaccine-specific T cell responses in blood. Total ARG1-specific CD4+ (black) and CD8+ (grey) T cell responses in peripheral blood mononuclear cells (PBMCs) at baseline and on treatment. The data were quantified by flow cytometry by an increased expression of interferon (IFN)γ, IFNγ + TNFα, and TNFα after five-hour peptide stimulation. A detailed cytokine expression profile is shown in Supplementary Figure 1. The values indicate specific responses subsequent to substraction of background values (n=10). N/A, Not available.

Figure 4

Spider plot showing changes in tumor size on evaluation scans for each patient. Patients were evaluated every three months. Numbers indicate patient ID. SD, stable disease; PD, progressive disease.

Figure 5

Overall survival and progression-free survival. mPFS, median progression-free survival; mOS, median overall survival.