Abstract P21: VISTA a potential new Immuno-oncology therapeutic target to treat human Acute Myeloid Leukemia
Authors: Thierry Guillaudeux, Shaarwari Sridhar, Emily Frazier, Yulia Ovechkina, Shawn Iadonato
Journal: Blood Cancer Discovery (2024)

Abstract V-domain Immunoglobulin Suppressor of T cell Activation (VISTA/PD-1H) is a co-inhibitor molecule of the B7 family member highly expressed on circulating and intra-tumoral myeloid cells. VISTA is a negative checkpoint protein that inhibits anti-tumor T cell responses. VISTA expression has been associated with poor overall survival in multiple solid tumors and is also described as a potential mediator of resistance to anti-CLTA-4 and anti-PD1 therapies. VISTA expression was also investigated in hematological tumors and described as highly expressed on blasts including leukemic stem cells from AML patients. Therefore, VISTA is a potentially new therapeutic target for cancer immunotherapy in this indication. Kineta has developed a fully human monoclonal antibody targeting VISTA, KVA12123, currently evaluated in a Phase 1/2 clinical trial alone and in combination with pembrolizumab in cancer patients with advanced solid tumors. Supported with previous published data on VISTA expression and function in myeloid leukemia, we also believe that our lead therapeutic anti-VISTA antibody could be a promising drug for AML patients. Therefore, we have tested in vivo, in a Kasumi-3 AML disseminated tumor model, the efficacy of our antibody alone or in combination with standard of care therapy, cytarabine and doxorubicin. The Kasumi-3 cell line exhibits a high level of VISTA expression on its cell surface, like leukemic cells in AML patients. Female NOD-scid mice were first inoculated with Kasumi cells via tail vein injection, and tumor engraftment was evaluated at different time points in the blood, spleen and bone marrow to monitor engraftment using CD34, CD33, CD45 and HLA-DR cell surface expression markers. Then, when tumor burden was high, standard of care treatment (5 doses of 16mg/kg AraC by IV injections and 3 doses of 0.5mg/kg Dox by IV injections) was initiated in indicated groups for 5 cycles, before starting treatment with KVA12 for the rest of the study. Tumor engraftment was tested after chemotherapy alone to evaluate the efficacy before starting treatment with our antibody. Our results showed that untreated mice had higher number of Kasumi-3 cells in the blood when compared to chemotherapy treated mice. Two backbone versions of our antibody were then tested, a human IgG1 – KVA12123 and a human IgG4 - KVA12402, at 30mg/kg IP injections twice a week for 5 weeks. Our data showed that KVA12123 and KVA12402 as single agents and in combination with chemotherapy reduced Kasumi-3 tumor load in the blood, spleen and bone marrow within the groups and significantly improved survival when compared to IgG1 control groups. These data indicate that anti-VISTA targeted therapy should be evaluated in myeloproliferative disorders like AML alone or in combination with standard of care. Citation Format: Thierry Guillaudeux, Shaarwari Sridhar, Emily Frazier, Yulia Ovechkina, Shawn Iadonato. VISTA a potential new Immuno-oncology therapeutic target to treat human Acute Myeloid Leukemia [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P21.