Development and Mechanistic Studies of an Engineered Human Therapeutic to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors One of the most common lesions observed across a broad number of cancers is the homozygous genetic deletion of methylthioadenosine phosporylase (MTAP), an enzyme that normally functions in amino acid and nucleotide recycling pathways. Deletion of MTAP in tumors results in the accumulation and secretion of its substrate methylthioadenosine (MTA). It is established that MTA is a very potent immunosuppressive molecule; importantly in preliminary studies our lab obtained strong in vivo evidence from multiple murine tumor models that the production of MTA by MTAPnull/low tumors strongly attenuates anti-tumor immune responses. This proposal describes an interdisciplinary team effort at the University of Texas at Austin detailing the development of a novel biologic cancer therapeutic, to reverse the immunosuppressive effects of MTA and aid in the treatment of patients with MTAPnull/low tumors as a key biomarker. In preliminary studies we have demonstrated that administration of an engineered human MTA degrading therapeutic (based on the human MTAP) can reverse the deleterious effects of MTA on lymphocytes in vitro, drastically retards the growth or elicits complete remissions of MTAP null murine cancer allografts and restores populations of T cells in both the tumor and tumor draining lymph node (TDLN) and demonstrates additive/synergistic effects when used in combination with existing immune checkpoint inhibitors. The evidence that the consequence of MTAP deletion acts to suppress immune effector cells and promote tolerogenic stromal cell phenotypes through the buildup of MTA now suggests a clear mechanism for why this is one of the more common gene deletions observed in cancer. Overall, we hypothesize that MTAP deletions in cancers act as an immune checkpoint that can be reversed therapeutically by enzymatic degradation of MTA in the tumor microenvironment using an engineered human methylthioadenosine phosphorylase. The work proposed here will seek to: (i) elucidate the cellular immunology and the biochemical/metabolomic and signaling mechanism(s) through which elevated extracellular MTA suppresses immune function; (ii) help clarify how MTA- mediated methyltransferase inhibition and remodeling of metabolism together with (likely secondarily) activation of the purinergic receptors impact lymphocytes; (iii) examine the efficacy of combinatorial treatments using standard of care antibody immune checkpoint inhibitors and very importantly (iv) develop an optimized MTA degrading drug that has the requisite pharmacological properties for late/stage preclinical/clinical administration..
Approximately 27% of all cancers exhibit methylthioadenosine phosporylase (MTAP deletion/deficiency) which results in methylthioadenosine (MTA) accumulation in the tumor microenvironment that acts to potently inhibit normal immune effector cells from eradicating malignant cells. We have demonstrated that administration of an engineered human MTA degrading enzyme therapeutic can reverse the deleterious effects of MTA on lymphocytes in vitro, drastically retard the growth or elicit complete remissions of murine cancer allografts displaying the MTAP null biomarker, and restore populations of T cells in both the tumor and tumor draining lymph node and has additive/synergistic effects when used in combination with existing immune checkpoint inhibitors. The work proposed here will further detail the novel mechanism(s) of action of MTA, examine the efficacy of combinatorial treatments using standard of care antibody immune checkpoint inhibitors and very importantly develop an optimized MTA degrading drug that has the requisite pharmacological properties for late/stage preclinical/clinical administration.
