MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma

• DOI: 10.1136/jitc-2019-000262
• Publication Date: 2020-05-08T12:06:21Z
• Authors: Victor H Engelhard; Rebecca C Obeng; Kara L Cummings; Gina R Petroni; Angela L Ambakhut...; Kimberly A Chiane...; Kelly T Smith; Amanda Lulu; Nikole Varhegyi; Mark E Smolkin; Paisley Myers; Keira E Mahoney; Jeffrey Shabanowitz; Nico Buettner; Emily H Hall; Kathleen Haden; Mark Cobbold; Donald F Hunt; Geoffrey Weiss; Elizabeth Gaughan; Craig L Slingluff...
• Keywords: ELISPOT; Phosphopeptide

Background Phosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized CD8 T-cells. These are promising targets for immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose this study was to characterize second phosphopeptide, breast antiestrogen resistance 3 (BCAR3), evaluate safety immunogenicity novel immunotherapic vaccine comprising either or both these phosphorylated peptides. Methods BCAR3 protein evaluated in melanoma cell lines Western blot, recognition T-cells specific peptide (pBCAR3 126-134 ) determined 51 Cr release assay intracellular cytokine staining. Human tumor explants were also mass spectrometry presentation pIRS2 pBCAR3 For the clinical trial, participants with resected stage IIA–IV vaccinated 6 times over 12 weeks incomplete Freund’s adjuvant Hiltonol (poly-ICLC). Adverse events (AEs) coded based National Cancer Institute (NCI) Common Terminology Criteria Events (CTCAE) V.4.03, provision early termination if dose-limiting toxicity (DLT) rates exceeded 33%. enrollment target evaluable immune response each peptide. T-cell responses assessed interferon-γ ELISpot assay. Results immunogenic vivo mice, vitro normal human donors, controlled outgrowth xenograft. 1097-1105 hepatocellular carcinoma tumors. In 15 enrolled. All had grade 1 treatment-related AEs, but there no 3–4 DLTs deaths study. induced 5/12 patients (42%, 90% CI 18% 68%) 2/12 (17%, 3% 44%). Conclusion This supports vaccines containing cancer-associated phosphopeptides , data support continued development therapy targeting phosphopeptides. Future studies will define ways further enhance magnitude durability phosphopeptide-specific responses. Trial registration number NCT01846143