Telomerase peptide cancer vaccine(Genovax SRL)

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.

Immune checkpoint inhibitors such as monoclonal antibodies (mAbs) are amongst the most important breakthroughs in cancer therapeutics. However, high cost and short acting time limits its affordability and clinical application. Therefore, an economical and durable alternative is urgently needed. Previously, we identified an IL-17RB targeting mAb which intercepts IL-17B/IL-17RB signal transduction and suppresses tumorigenesis in many types of cancer. We reason that active immunity against the antigenic epitope of IL-17RB can reproduce the anti-cancer effect of mAbs with better sustainability. Here, we present a cancer vaccine composed of multiple synthesized epitope peptides chemically conjugated onto CRM197, a highly immunogenic carrier protein. Combining mass spectrometry with immunoassay, we standardized hapten density determination and optimized vaccine design. Furthermore, orthotopically transplanted syngeneic mouse tumor 4T1 showed that administration of this vaccine therapeutically mitigates primary cancer growth as well as distance metastasis. In conclusion, we demonstrate preparation, characterization and pre-clinical application of a novel peptide cancer vaccine.