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

• DOI: 10.1136/jitc-2021-sitc2021.772
• Publication Date: 2021-11-09T15:26:37Z
• Authors: Mathieu Gigoux; Roberta Zappasodi; Joseph Park; Cansu Cimen Bozkus; Levi Mangarin; David Redmond; Svena Verma; Sara Schad; Mariam George; Divya Venkatesh; Arnab Ghosh; Zaki Molvi; Baransel Kamaz; Anna Marneth; William Duke; Matthew Leventhal; Max Jan; Vincent Ho; Gabriela Hobbs; Trine Knudsen; Vibe Skov; Lasse Kjær; Thomas Larsen; Dennis Hansen; R. Lindsley; Hans Hasselbalch; Jacob Grauslund; Mads Andersen; Morten Holmstrom; Timothy Chan; Raajit Rampal; Omar Abdel-Wahab; Nina Bhardwaj; Ann Mullally; Jedd Wolchok; Taha Merghoub
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

<h3>Background</h3> The majority of JAK2V617F-negative myeloproliferative neoplasms (MPN) have disease-initiating frameshift mutations in calreticulin (CALR) resulting a common novel C-terminal mutant fragment (CALRMUT), representing an attractive source neoantigens for cancer vaccines. However, studies shown that CALRMUT-specific T cells are rare CALRMUT MPN patients, but the underlying reasons this phenomenon unknown. We speculate is due to increased chance immune-mediated tumor rejection by individuals expressing one these MHC-I alleles such disease never clinically manifests. As consequence allele restriction, we reasoned patients would not efficiently respond vaccines composed neoantigen, could do so when immunized with properly epitope-optimized heteroclitic peptide vaccine approach. <h3>Methods</h3> examined frequency from two independent cohorts identify under-represented alleles. These were assessed their ability bind CALRMUT-derived peptides using NetMHC and subsequently validated experimentally healthy donors having received (clinical trial NCT03566446) determine if potentiating immunogenicity against antigen. Epitope-optimized variants neoantigen identified tested vitro human PBMCs vivo mice mount immune response non-modified neoantigen. <h3>Results</h3> observed present neoepitopes high affinity patients. Heteroclitic specifically designed patient elicited cross-reactive CD8+ cell PBMC samples otherwise unable matched weakly immunogenic native peptides. also modeled effect C57BL/6J mice, which fragment, can upon immunization was further amplified combining blockade checkpoint molecule PD-1. <h3>Conclusions</h3> Our study shows able demonstrating haplotype major mechanism passive immune-evasion MPN. show antigen overcome limitation. <h3>Ethics Approval</h3> Approval obtained use patient-derived specimens access clinical data extracted charts Institutional Review Boards at Memorial Sloan Kettering Cancer Center, Dana-Farber Institute Massachusetts General Hospital, as well Danish Regional Science Ethics Committee.