Development and Mechanistic Studies of an Engineered Human Enzyme to Abrogate Immune Suppression due to Elevated Methylthioadenosine (MTA) by MTAP null/low Tumors

一种工程化人类酶的开发和机制研究，用于消除 MTAP 无效/低肿瘤导致的甲硫腺苷 (MTA) 升高引起的免疫抑制

• 批准号: 10188468
• 负责人: Everett Stone
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188468
• 关键词: Ablation; Adenosine; Adopted; Agonist; Allografting; Amino Acids; Animals; Antibodies; Antibody Therapy; Apoptotic; Attenuated; Biochemical; Biochemistry; Biological; Biological Markers; CT26; Cancer Model; Cell Differentiation process; Cellular Immunology; Clinical; Clinical Research; Colon Carcinoma; Combined Modality Therapy; Data; Development; Disease remission; Effector Cell; Engineering; Enzymes; Excision; Exhibits; Formulation; Frequencies; Gene Deletion; Genetic; Goals; Growth; Human; Human Engineering; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapeutic agent; Impairment; In Vitro; In complete remission; Lesion; Lymphocyte; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Methyltransferase; Modality; Modeling; Mus; Nucleotides; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase I/II Clinical Trial; Phenotype; Phosphorylases; Play; Population; Production; Property; Proteomics; Purinergic P1 Receptors; Purinoceptor; Recycling; Research Proposals; Role; Serum; Signal Pathway; Signal Transduction; Stromal Cells; T-Cell Proliferation; T-Lymphocyte; TP53 gene; Testing; Texas; Therapeutic; Therapeutic Agents; Toxicology; Treatment Efficacy; Tumor-infiltrating immune cells; Universities; Up-Regulation; Work; anti-CTLA4; anti-tumor immune response; austin; base; biomarker-driven; cancer cell; cancer therapy; checkpoint inhibition; chromatin remodeling; clinical candidate; clinical development; clinical translation; combinatorial; draining lymph node; drug candidate; efficacy evaluation; experience; extracellular; immune checkpoint; immune function; in vivo; leukemia; melanoma; metabolomics; mouse model; novel; pharmacokinetics and pharmacodynamics; pre-clinical; programmed cell death protein 1; standard of care; therapeutic development; therapeutic enzyme; therapeutic protein; tool; treatment effect; tumor; tumor eradication; tumor growth; tumor immunology; tumor microenvironment

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..

一种工程人类治疗药物的开发和机理研究