444 MHC-I skewing in mutant calreticulin-positive myeloproliferative neoplasms is countered by heteroclitic peptide cancer vaccination. (9th November 2020)

• Record Type: Journal Article
• Authors: Gigoux, Mathieu; Zappasodi, Roberta; Park, Joseph; Pourpe, Stephane; Ghosh, Arnab; Bozkus, Cansu Cimen; Mangarin, Levi; Redmond, David; Verma, Svena; Schad, Sara; Duke, William; Jan, Max; Leventhal, Matthew; Ho, Vincent; Hobbs, Gabriela; Knudsen, Trine Alma; Skov, Vibe; Kjær, Lasse; Larsen, Thomas Stauffer; Hansen, Dennis Lund; Coleman Lindsley, R; Hasselbalch, Hans; Grauslund, Jacob; Andersen, Mads; Holmström, Morten; Chan, Timothy; Rampal, Raajit; Abdel-Wahab, Omar; Bhardwaj, Nina; Wolchok, Jedd; Mullally, Ann; Merghoub, Taha;
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 3
• Page Start: A470
• Page End: A470
• Publication Date: 2020-11-09
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/jitc-2020-SITC2020.0444
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: The majority of JAK2V617F-negative myeloproliferative neoplasms (MPN) have disease-initiating frameshift mutations in calreticulin (CALR) resulting in a common novel C-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in CALRMUT MPN patients, but the underlying reasons for this phenomenon are unknown. Methods: In this study, we examine class-I major histocompatibility complex (MHC-I) allele frequency in CALRMUT MPN patients from two independent cohorts and observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are under-represented in CALRMUT MPN patients. We speculate that this is due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles such that the disease never clinically manifests. As a consequence of this MHC-I allele restriction, we reasoned that CALRMUT MPN patients would not efficiently respond to cancer vaccines composed of the CALRMUT fragment, but could do so when immunized with a properly modified CALRMUT heteroclitic peptide vaccine approach. Results: We found that heteroclitic CALRMUT peptides specifically designed for CALRMUT MPN patient MHC-I alleles efficiently elicited a cross-reactive CD8+ T cell response in human PBMC samples otherwise unable to respond to the matched weakly immunogenic CALRMUT native peptides. We also modeled this effect in mice and observed that C57BL/6J mice, which are unable to mount an immune response to the human CALRMUT fragment, can mount a cross-reactive CD8+ T cell response against a CALRMUT-derived peptide upon heteroclitic peptide immunization and this was further amplified by combining the heteroclitic peptide vaccine with blockade of the immune checkpoint molecule PD-1. Conclusions: Together, our data underscore the therapeutic potential of heteroclitic peptide-based cancer vaccines in CALRMUT MPN patients. Ethics Approval: Approval was obtained for the use of patient-derived specimens and access to clinical data extracted from patient charts by the Institutional Review Boards at Memorial Sloan Kettering Cancer Center, the Dana-Farber Cancer Institute and the Massachusetts General Hospital, as well as by the Danish Regional Science Ethics Committee. Mouse experiments were performed in accordance with institutional guidelines under a protocol approved by the Memorial Sloan-Kettering Cancer Center Institutional Animal Care and Use Committee.