Development of Epitope-Focused Tumor Vaccine to Prevent Escape from Immune Surveillance by the NKG2D Pathway
Technical Report,15 Aug 2016,14 Aug 2017
Dana-Farber Cancer Institute Boston United States
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MICA is a stress proteins that is frequently expressed by many different types of human cancers due to genomic damage and aberrant signaling. Expression of MICA marks stressedinfected cells for elimination by cytotoxic lymphocytes, in particular NK cells and CD8 T cells. Engagement of the NKG2D receptor by MICA triggers NK cell mediated cytolysis and provides a costimulatory signal in T cells. Many cancers evade this important pathway through proteolytic shedding of MICA. Shed MICA is associated with progression in many human solid and hematological malignancies. The shedding process targets the membrane-proximal alpha3 domain of MICA through the coordinated action of the disulfide isomerase ERp5 and several proteases. MICA antibodies from patients responding to an autologous cancer vaccine combined with CTLA-4 blockade were found to sterically inhibit shedding through binding to the MICA alpha3 domain. The goal of this project was to develop a novel cancer vaccine which inhibits this important immune evasion mechanism. The specific aims of this proposal were to 1. Generate MICA alpha3 domain vaccine, 2. Test the therapeutic activity of vaccine in melanoma mouse model, 3. Investigation of immunological mechanisms leading to protective effect of the vaccine. Preliminary data show that a vaccine targeting the MICA alpha3 domain indeed induces polyclonal antibodies that strongly inhibit MICAB shedding by cancer cells. This vaccine has significant efficacy in a mouse model of melanoma in controlling experimental lung metastasis and subcutaneous tumor growth. Dissection of the immunological mechanisms showed both CD8 T cells and NK cells to be important for the protective effect of the vaccine. This vaccine could be used to prevent the emergence of metastases in high-risk patients, for example in patients following surgical removal of a locally advanced melanoma who are at a high-risk for disease recurrence.
- Medicine and Medical Research