Development of a tumor-activated IL12 prodrug to treat solid tumors

开发肿瘤激活的 IL12 前药来治疗实体瘤

基本信息

批准号：
10558656
负责人：
Benjamin Moon
金额：
$ 4.68万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558656
关键词：
Accounting Acidity Adoptive Transfer Adverse effects Affinity Antibodies Antitumor Response Binding Biodistribution Biological Assay Biological Markers Blood Body Weight Body Weight decreased Body Weights and Measures C57BL/6 Mouse CD8-Positive T-Lymphocytes CD8B1 gene Cause of Death Cell Differentiation process Cells Cellular Immunity Cessation of life Clinical Clinical Trials Combined Modality Therapy Complex Data Development Dose Drug Design Drug Kinetics Effector Cell Enzymes Exposure to Future Goals Histology Homeostasis Human Hypoxia IFNGR1 gene Immune Immune checkpoint inhibitor Immune response Immunotherapeutic agent Immunotherapy Impairment Interferon Type II Interleukin-12 Kinetics Lymphoid Cell MC38 MMP14 gene Malignant Neoplasms Measures Mediating Modality Modeling Molecular Molecular Conformation Monitor Mus Natural Killer Cells Near-infrared optical imaging Neoplasm Metastasis Patients Pharmaceutical Preparations Play Pre-Clinical Model Prodrugs Production Prognostic Marker Property Refractory Role Schedule Serum Signal Pathway Signal Transduction Site Solid Neoplasm Supporting Cell T-Cell Activation T-Lymphocyte Testing Tissue Sample Toxic effect Tumor Immunity Tumor-infiltrating immune cells United States antitumor effect cancer immunotherapy cell type clinical development conventional therapy cytokine flexibility genetic signature immune checkpoint improved in vivo insight interleukin-12 receptor neoplastic cell novel novel therapeutics overexpression preclinical study preclinical trial prevent response single-cell RNA sequencing subcutaneous success synergism tumor tumor eradication tumor microenvironment

项目摘要

Project Summary/Abstract: Despite recent advances in cancer immunotherapy, solid tumors remain largely refractory to treatment due to disruption of immune homeostasis by the tumor microenvironment (TME). Within the TME, a combination of hypoxia, acidity, suppressive cells, and immune checkpoints leads to poor differentiation of type I effector cells, preventing the development of a robust immune response. IL12 is a naturally produced cytokine that can directly induce type I, cell-mediated immunity through the IL12Rβ1/IL12Rβ2 complex on innate lymphoid cells (ILCs) and T cells. IL12 has been remarkably successful against solid tumors in preclinical trials, but its clinical development has been impaired by lethal toxicity due to systemic immune overactivation. I have developed a novel IL12-based prodrug (proIL12) that displays no noticeable toxicity in vivo but maintains full antitumor efficacy. The kinetics and cellular mechanism of proIL12 must still be ascertained, but preliminary data suggests T cells play a critical role and IFNγ is the main cytokine induced. Therefore, I hypothesize that proIL12 circulates in inert prodrug form until activated by tumor-specific enzymes, at which point it activates T cells directly through IL12 receptor and secondarily through IFNγ production. To test my hypothesis, I will first validate proIL12’s drug profile by determining an optimal dosing schedule, monitoring tumor-specific activation, and measuring toxicity. Then, I will explore which specific cell subtypes among ILCs and T cells are necessary to reject tumors. Finally, I will independently assess the downstream role of IFNγ in coordinating the proIL12 response. By systematically characterizing both physical and mechanistic properties of proIL12, I will not only prepare it for further clinical development but also inform future steps such as combination therapies or prognostic markers. As a whole, my study will produce a tolerable immunotherapeutic agent capable of reversing TME-induced immune disarray to eliminate solid tumors.

项目摘要/摘要：尽管癌症免疫疗法最近取得了进展，但由于以下原因，实体瘤在很大程度上仍然难以治疗：肿瘤微环境 (TME) 破坏免疫稳态，是以下因素的结合。缺氧、酸性、抑制性细胞和免疫检查点导致 I 型效应细胞分化不良， IL12 是一种天然产生的细胞因子，可以直接抑制免疫反应的发展。通过先天淋巴细胞 (ILC) 上的 IL12Rβ1/IL12Rβ2 复合物诱导 I 型细胞介导的免疫 IL12 在临床前试验中针对实体瘤取得了巨大成功，但其临床由于全身免疫过度激活，致死毒性损害了发育。新型基于 IL12 的前药 (proIL12)，在体内没有表现出明显的毒性，但保持完全的抗肿瘤作用 proIL12 的动力学和细胞机制仍有待确定，但初步数据表明。 T 细胞发挥着关键作用，而 IFNγ 是诱导的主要细胞因子，因此我认为 proIL12 会发生重大变化。呈惰性前药形式，直到被肿瘤特异性酶激活，此时它通过直接激活 T 细胞为了验证我的假设，我将首先验证 proIL12 的药物。通过确定最佳给药方案、监测肿瘤特异性激活和测量毒性来了解情况。然后，我将探讨 ILC 和 T 细胞中哪些特定的细胞亚型对于排斥肿瘤是必需的。我将系统地独立评估 IFNγ 在协调 proIL12 反应中的下游作用。表征 proIL12 的物理和机械特性，我不仅会为进一步的临床做好准备发展，但也为未来的步骤提供信息，例如联合疗法或预后标志物。研究将产生一种可耐受的免疫治疗剂，能够逆转 TME 诱导的免疫紊乱消除实体瘤。