Abstract LB-A18: The frequent tumor deletion of MTAP is a newly recognized potent immune checkpoint that is effectively reversed by a human methylthioadenosine degrading drug candidate

Our lab has obtained strong in vivo evidence from multiple murine tumor models that the production of methylthioadenosine (MTA) by methylthioadenosine phosphorylase (MTAP) deficient tumors potently attenuates anti-tumor immune responses, validating its role as a potent immunosuppressive molecule. We demonstrate that administration of an engineered human MTA degrading enzyme therapeutic reverses the deleterious effects of MTA on lymphocytes in vitro, and in vivo drastically impedes the growth of MTAP deficient tumors including MTAP-/- leukemia (L1210), MTAP low colon carcinoma (CT26) and an engineered MTAP-/- B16-F10 melanoma. As a single agent our therapeutic candidate elicits a large fraction of complete and durable responses in animals with established tumors, correlating with significant increases in the populations of effector T cells in both the tumor and tumor draining lymph node. We also note that enzyme treatment displays synergism in combination with existing immune checkpoint inhibitors. Despite the remarkable success of immune checkpoint inhibitors such as anti-PD1 and anti-CTLA-4 antibodies, a large fraction of tumors do not respond to immunotherapy due to additional suppressive mechanisms such as adenosinergic signaling. Approximately 15% of all cancers exhibit homozygous MTAP deletions resulting in accumulation and secretion of the adenosine (ADO) analog, MTA. Patients with cancer MTAP deletions show reduced tumor infiltrating lymphocytes (TILs) and poor overall survival in multiple tumor types. Recent work has even suggested that MTAP loss may confer resistance to antibody immune checkpoint inhibitors. Although MTA is reported to be an ADO receptor agonist, purinergic signaling alone does not explain the distinct immune suppression associated with increased MTA. In vitro, MTA (but not ADO) strongly inhibits the proliferation and viability of both CD4+ and especially CD8+ murine T cells. Similarly, treatment with ADO receptor antagonists does not restore proliferation or reverse the cytotoxicity of MTA. Only exogenous administration of MTA degrading enzymes was able to reverse these effects, indicating that MTA impacts the viability and proliferation of T cells by a mechanism independent of ADO receptor signaling. Quantitative proteomic data suggests instead that MTA acts, at least in part, via the inhibition of methyltransferases, chromatin remodeling and upregulation of P53/apoptotic pathways in lymphocytes. Collectively our data suggest that enzymatic depletion of MTA represents a unique opportunity for a biomarker driven (namely, tumor MTAP status) immunotherapeutic modality. The evidence that the consequence of MTAP deletion acts to suppress immune effector cells and promote tumor tolerance through the buildup of MTA now suggests a clear mechanism for why this is one of the more common gene deletions observed in cancer. Citation Format: Donjeta Gjuka, George Georgiou, Everett M Stone. The frequent tumor deletion of MTAP is a newly recognized potent immune checkpoint that is effectively reversed by a human methylthioadenosine degrading drug candidate [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A18. doi:10.1158/1535-7163.TARG-19-LB-A18