In this analysis, SBRT achieves similar disease control outcomes as IMRT, with less acute toxicity. This suggests SBRT is an attractive technique for pancreatic radiotherapy because of improved convenience and tolerability with equivalent efficacy. However, the lack of observed advantages in disease control with this moderate-dose SBRT regimen may suggest a role for increasing SBRT dose, if this can be accomplished without significant increase in toxicity.
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.
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