Journal Article

444 MHC-I skewing in mutant calreticulin-positive myeloproliferative neoplasms is countered by heteroclitic peptide cancer vaccination

Andersen, Mads, Duke, William, Mangarin, Levi, Skov, Vibe, Kjær, Lasse, Chan, Timothy, Verma, Svena, Larsen, Thomas Stauffer, Wolchok, Jedd, Ghosh, Arnab, Hasselbalch, Hans, Gigoux, Mathieu, Pourpe, Stephane, Mullally, Ann, Park, Joseph, Grauslund, Jacob, Abdel-Wahab, Omar, Bhardwaj, Nina, Zappasodi, Roberta, Hobbs, Gabriela, Leventhal, Matthew, Merghoub, Taha, Knudsen, Trine Alma, Coleman Lindsley, R, Rampal, Raajit, Schad, Sara, Redmond, David, Hansen, Dennis Lund, Ho, Vincent, Bozkus, Cansu Cimen, Jan, Max, Holmström, Morten

2020

Overview

BackgroundThe 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.MethodsIn 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.ResultsWe 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.ConclusionsTogether, our data underscore the therapeutic potential of heteroclitic peptide-based cancer vaccines in CALRMUT MPN patients.Ethics ApprovalApproval 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.

• Publisher: BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Cancer / Cancer vaccines / Immunotherapy / Patients / Peptides / Tumors / Vaccines