PMID- 36911725 OWN - NLM STAT- MEDLINE DCOM- 20230314 LR - 20230327 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 14 DP - 2023 TI - An arginase1- and PD-L1-derived peptide-based vaccine for myeloproliferative neoplasms: A first-in-man clinical trial. PG - 1117466 LID - 10.3389/fimmu.2023.1117466 [doi] LID - 1117466 AB - INTRODUCTION: Arginase-1 (ARG1) and Programed death ligand-1 (PD-L1) play a vital role in immunosuppression in myeloproliferative neoplasms (MPNs) and directly inhibit T-cell activation and proliferation. We previously identified spontaneous T-cell responses towards PD-L1 and ARG1 derived peptide epitopes in patients with MPNs. In the present First-in-Man study we tested dual vaccinations of ARG1- derived and PD-L1-derived peptides, combined with Montanide ISA-51 as adjuvant, in patients with Janus Kinase 2 (JAK2) V617F-mutated MPN. METHODS: Safety and efficacy of vaccination with ARG1- derived and PD-L1-derived peptides with montanide as an adjuvant was tested in 9 patients with MPN The primary end point was safety and toxicity evaluation. The secondary end point was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT04051307). RESULTS: The study included 9 patients with JAK2-mutant MPN of which 8 received all 24 planned vaccines within a 9-month treatment period. Patients reported only grade 1 and 2 vaccine related adverse events. No alterations in peripheral blood counts were identified, and serial measurements of the JAK2V617F allelic burden showed that none of the patients achieved a molecular response during the treatment period. The vaccines induced strong immune responses against both ARG1 and PD-L1- derived epitopes in the peripheral blood of all patients, and vaccine-specific skin-infiltrating lymphocytes from 5/6 patients could be expanded in vitro after a delayed-type hypersensitivity test. In two patients we also detected both ARG1- and PD-L1-specific T cells in bone marrow samples at the end of trial. Intracellular cytokine staining revealed IFNgamma and TNFgamma producing CD4(+)- and CD8(+)- T cells specific against both vaccine epitopes. Throughout the study, the peripheral CD8/CD4 ratio increased significantly, and the CD8(+) TEMRA subpopulation was enlarged. We also identified a significant decrease in PD-L1 mRNA expression in CD14(+) myeloid cells in the peripheral blood in all treated patients and a decrease in ARG1 mRNA expression in bone marrow of 6 out of 7 evaluated patients. CONCLUSION: Overall, the ARG1- and PD-L1-derived vaccines were safe and tolerable and induced strong T-cell responses in all patients. These results warrant further studies of the vaccine in other settings or in combination with additional immune-activating treatments. CI - Copyright (c) 2023 Grauslund, Holmstrom, Martinenaite, Lisle, Glockner, El Fassi, Klausen, Mortensen, Jorgensen, Kjaer, Skov, Svane, Hasselbalch and Andersen. FAU - Grauslund, Jacob Handlos AU - Grauslund JH AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. FAU - Holmstrom, Morten Orebo AU - Holmstrom MO AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. AD - Institute for Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. FAU - Martinenaite, Evelina AU - Martinenaite E AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. AD - Research and Development, IO Biotech ApS, Copenhagen, Denmark. FAU - Lisle, Thomas Landkildehus AU - Lisle TL AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. FAU - Glockner, Hannah Jorinde AU - Glockner HJ AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. FAU - El Fassi, Daniel AU - El Fassi D AD - Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Klausen, Uffe AU - Klausen U AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. AD - Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. FAU - Mortensen, Rasmus E J AU - Mortensen REJ AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. FAU - Jorgensen, Nicolai AU - Jorgensen N AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. FAU - Kjaer, Lasse AU - Kjaer L AD - Department of Hematology, Zealand University Hospital, Roskilde, Denmark. FAU - Skov, Vibe AU - Skov V AD - Department of Hematology, Zealand University Hospital, Roskilde, Denmark. FAU - Svane, Inge Marie AU - Svane IM AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. FAU - Hasselbalch, Hans Carl AU - Hasselbalch HC AD - Department of Hematology, Zealand University Hospital, Roskilde, Denmark. FAU - Andersen, Mads Hald AU - Andersen MH AD - National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. AD - Institute for Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark. LA - eng SI - ClinicalTrials.gov/NCT04051307 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230223 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Monatide (IMS 3015)) RN - 0 (B7-H1 Antigen) RN - 0 (Adjuvants, Immunologic) RN - 0 (Epitopes) RN - 0 (Peptides) RN - 0 (Vaccines, Subunit) RN - 0 (RNA, Messenger) SB - IM MH - Humans MH - B7-H1 Antigen/metabolism MH - *Neoplasms/drug therapy MH - *Myeloproliferative Disorders/genetics MH - Adjuvants, Immunologic MH - Epitopes MH - Peptides MH - Vaccines, Subunit MH - RNA, Messenger PMC - PMC9996128 OTO - NOTNLM OT - PD-L1 OT - arginase-1 OT - cancer immune therapy OT - immune modulatory vaccines OT - myeloproliferative neoplasms COIS- MA is named as an inventor on various patent applications relating to therapeutic uses of PD-L1 and Arginase peptides. These patent applications are assigned to the company IO Biotech ApS, which is developing immune-modulating cancer treatments. MA is founder, shareholder and advisor of IO Biotech ApS. EM is an employee at IO Biotech ApS. IS is co-founder, shareholder and advisor of 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. The handling editor NO declared a shared parent affiliation with the authors, MHA, JHG, MOH, EM, TL, HJG, DEF, UK, REM, NJ, IMS, at the time of review. EDAT- 2023/03/14 06:00 MHDA- 2023/03/15 06:00 PMCR- 2023/01/01 CRDT- 2023/03/13 04:29 PHST- 2022/12/06 00:00 [received] PHST- 2023/02/06 00:00 [accepted] PHST- 2023/03/13 04:29 [entrez] PHST- 2023/03/14 06:00 [pubmed] PHST- 2023/03/15 06:00 [medline] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2023.1117466 [doi] PST - epublish SO - Front Immunol. 2023 Feb 23;14:1117466. doi: 10.3389/fimmu.2023.1117466. eCollection 2023.