MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma
| Autor: | Rebecca C. Obeng, Nikole Varhegyi, Kimberly A. Chianese-Bullock, Gina R. Petroni, Geoffrey R. Weiss, Elizabeth M. Gaughan, Angela L. Ambakhutwala, Emily H. Hall, Kelly T. Smith, Mark Cobbold, Victor H. Engelhard, Kara L. Cummings, Amanda M. Lulu, Paisley T. Myers, Mark E. Smolkin, Nico Buettner, Craig L. Slingluff, Jeffrey Shabanowitz, Kathleen Haden, Donald F. Hunt, Keira E. Mahoney |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Phosphopeptides 0301 basic medicine Cancer Research Skin Neoplasms medicine.medical_treatment Pilot Projects immunogenicity CD8-Positive T-Lymphocytes Mice Immunogenicity Vaccine 0302 clinical medicine Cancer immunotherapy antigens vaccine Guanine Nucleotide Exchange Factors Immunology and Allergy RC254-282 Clinical/Translational Cancer Immunotherapy Aged 80 and over Phosphopeptide Immunogenicity Neoplasms. Tumors. Oncology. Including cancer and carcinogens Common Terminology Criteria for Adverse Events Middle Aged Oncology 030220 oncology & carcinogenesis Vaccines Subunit Molecular Medicine Female Immunotherapy Adult Immunology Mice Transgenic Cancer Vaccines Proof of Concept Study 03 medical and health sciences Breast cancer Antigen Antigens Neoplasm Cell Line Tumor HLA-A2 Antigen melanoma medicine Animals Humans Adaptor Proteins Signal Transducing Aged Pharmacology business.industry Cancer vaccination medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology Insulin Receptor Substrate Proteins Cancer research business neoplasm |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 8, Iss 1 (2020) |
| ISSN: | 2051-1426 |
| DOI: | 10.1136/jitc-2019-000262 |
| Popis: | BackgroundPhosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides.MethodsPhosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3126-134) was determined by51Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA–IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund’s adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay.ResultspBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3126-134controlled outgrowth of a tumor xenograft. The pIRS21097-1105peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3–4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS21097-1105peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3126-134peptide in 2/12 patients (17%, 90% CI 3% to 44%).ConclusionThis study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3126-134and pIRS21097-1105, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses.Trial registration numberNCT01846143 |
| Databáze: | OpenAIRE |
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