Vivian G. Oehler, MD
Project Titile: Characterizing myeloproliferative neoplasm neoantigens and T cell responses for therapeutic applications
Classical myeloproliferative neoplasms (MPNs) originate from an early hematopoietic progenitor (“MPN stem cell”) that generally has acquired one of three driver mutations: JAK2 V617F, MPL W515L/K/A/R or insertion-deletion mutations in CALR. Existing therapies, including targeted JAK2 inhibition, alleviate MPN symptoms, but rarely produce cures. In contrast, T cell-based immunotherapy could also be highly MPN-specific and curative, if targeted against novel antigens (neoantigens) derived from mutated regions of MPN drivers and/or other mutated proteins present in MPN stem cells. We have developed a method to identify neoantigens in acute myeloid leukemia, which we now propose using to identify neoantigens from recurrent MPN mutations. We will determine which neoantigens occur on MPN progenitors and, ultimately, on MPN stem cells. In parallel, we will interrogate MPN-specific T cells in patient blood and marrow samples to determine the frequency of spontaneous T cell responses against MPN neoantigens and the degree and type of T cell inhibition in MPNs. The proposed studies will inform the development of MPN neoantigen-directed T cell immunotherapy, by identifying optimal targets for MPN stem cell eradication, a validated therapeutic approach (adoptive T cell therapy and/or vaccination) and the advisability of combining immune checkpoint inhibition with neoantigen-directed therapy.