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Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.

ABSTRACT: The majority of JAK2^V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-terminal mutant fragment (CALR^MUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALR^MUT-specific T cells are rare in patients with CALR^MUT MPN for unknown reasons. We examined class I major histocompatibility complex (MHC-I) allele frequencies in patients with CALR^MUT MPN from two independent cohorts. We observed that MHC-I alleles that present CALR^MUT neoepitopes with high affinity are underrepresented in patients with CALR^MUT MPN. We speculated that this was 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 manifested. As a consequence of this MHC-I allele restriction, we reasoned that patients with CALR^MUT MPN would not efficiently respond to a CALR^MUT fragment cancer vaccine but would when immunized with a modified CALR^MUT heteroclitic peptide vaccine approach. We found that heteroclitic CALR^MUT peptides specifically designed for the MHC-I alleles of patients with CALR^MUT MPN efficiently elicited a CALR^MUT cross-reactive CD8⁺ T cell response in human peripheral blood samples but not to the matched weakly immunogenic CALR^MUT native peptides. We corroborated this effect in vivo in mice and observed that C57BL/6J mice can mount a CD8⁺ T cell response to the CALR^MUT fragment upon immunization with a CALR^MUT heteroclitic, but not native, peptide. Together, our data emphasize the therapeutic potential of heteroclitic peptide-based cancer vaccines in patients with CALR^MUT MPN.

SUBMITTER: Gigoux M

PROVIDER: S-EPMC11182673 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.

Gigoux Mathieu M Holmström Morten O MO Zappasodi Roberta R Park Joseph J JJ Pourpe Stephane S Bozkus Cansu Cimen CC Mangarin Levi M B LMB Redmond David D Verma Svena S Schad Sara S George Mariam M MM Venkatesh Divya D Ghosh Arnab A Hoyos David D Molvi Zaki Z Kamaz Baransel B Marneth Anna E AE Duke William W Leventhal Matthew J MJ Jan Max M Ho Vincent T VT Hobbs Gabriela S GS Knudsen Trine Alma TA Skov Vibe V Kjær Lasse L Larsen Thomas Stauffer TS Hansen Dennis Lund DL Lindsley R Coleman RC Hasselbalch Hans H Grauslund Jacob H JH Lisle Thomas L TL Met Özcan Ö Met Özcan Ö Wilkinson Patrick P Greenbaum Benjamin B Sepulveda Manuel A MA Chan Timothy T Rampal Raajit R Andersen Mads H MH Abdel-Wahab Omar O Bhardwaj Nina N Wolchok Jedd D JD Mullally Ann A Merghoub Taha T

Science translational medicine 20220615 649

The majority of JAK2V617F-negative myeloproliferative neoplasms (MPNs) have disease-initiating frameshift mutations in calreticulin (CALR), resulting in a common carboxyl-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 patients with CALRMUT MPN for unknown reasons. We examined class I major histocompatibility complex (M ...[more]

PMID: 35704596

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Project description:BackgroundThe calreticulin (CALR) exon 9 mutations that are identified in 20% of patients with Philadelphia chromosome negative chronic myeloproliferative neoplasms (MPN) generate immunogenic antigens. Thus, therapeutic cancer vaccination against mutant CALR could be a new treatment modality in CALR-mutant MPN.MethodsThe safety and efficacy of vaccination with the peptide CALRLong36 derived from the CALR exon 9 mutations was tested in a phase I clinical vaccination trial with montanide as adjuvant. Ten patients with CALRmut MPN were included in the trial and received 15 vaccines over the course of one year. The primary end point was evaluation of safety and toxicity of the vaccine. Secondary endpoint was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT03566446).ResultsPatients had a median age of 59.5 years and a median disease duration of 6.5 years. All patients received the intended 15 vaccines, and the vaccines were deemed safe and tolerable as only two grade three AE were detected, and none of these were considered to be related to the vaccine. A decline in platelet counts relative to the platelets counts at baseline was detected during the first 100 days, however this did not translate into neither a clinical nor a molecular response in any of the patients. Immunomonitoring revealed that four of 10 patients had an in vitro interferon (IFN)-γ ELISPOT response to the CALRLong36 peptide at baseline, and four additional patients displayed a response in ELISPOT upon receiving three or more vaccines. The amplitude of the immune response increased during the entire vaccination schedule for patients with essential thrombocythemia. In contrast, the immune response in patients with primary myelofibrosis did not increase after three vaccines.ConclusionTherapeutic cancer vaccination with peptide vaccines derived from mutant CALR with montanide as an adjuvant, is safe and tolerable. The vaccines did not induce any clinical responses. However, the majority of patients displayed a marked T-cell response to the vaccine upon completion of the trial. This suggests that vaccines directed against mutant CALR may be used with other cancer therapeutic modalities to enhance the anti-tumor immune response.

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Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.

Publications

Calreticulin mutant myeloproliferative neoplasms induce MHC-I skewing, which can be overcome by an optimized peptide cancer vaccine.

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