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步，但实体瘤仍然很大程肿瘤微环境（TME）对免疫稳态的破坏。在TME中，结合了缺氧，酸度，抑制细胞和免疫定位点会导致I型效应细胞的分化差，防止出现强大的免疫响应的发展。 IL12是一种天然产生的细胞因子，可以直接通过IL12Rβ1/IL12Rβ2复合物在先天淋巴样细胞（ILC）上诱导I型，细胞介导的免疫学和T细胞。在临床前试验中，IL12对实体瘤取得了非常成功的成功，但其临床由于全身免疫过度活化而导致致命的毒性损害了发育。我已经开发了一个基于IL12的新型前药（Proil12），在体内没有明显的毒性，但保持完整的抗肿瘤功效。仍然必须确定PROIL12的动力学和细胞机制，但初步数据表明 T细胞起关键作用，IFNγ是主要的细胞因子诱导的。因此，我假设Proil12圆圈以惰性前药形式直至被肿瘤特异性酶激活，此时，它直接激活T细胞 IL12受体和通过IFNγ产生的继发。为了检验我的假设，我将首先验证Proil12的药物通过确定最佳剂量时间表，监测肿瘤特异性激活并测量毒性来概况。然后，我将探索ILC和T细胞之间哪些特定细胞亚型以拒绝肿瘤。最后，我将独立评估IFNγ在配位PROIL12响应中的下游作用。通过系统地表征Proil12的物理和机械性能，我不仅会为进一步的临床准备开发，但也可以为未来的步骤（例如组合疗法或预后标记）提供信息。总体而言，我的研究将产生可耐受的免疫治疗剂，能够逆转TME诱导的免疫膜片消除实体瘤。