Development of Programmable mRNA Circuits for Melanoma Immunotherapy

用于黑色素瘤免疫治疗的可编程 mRNA 电路的开发

基本信息

批准号：
10258632
负责人：
Ryan Sowell
金额：
$ 39.95万
依托单位：
STRAND THERAPEUTICS INC
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：
2021-05-17 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10258632
关键词：
Abscopal effect Address Adjuvant Adjuvant Therapy Adverse effects Adverse event American Animals Benchmarking Biological Bolus Infusion Cells Clinical Data Diagnosis Disease remission Distal Dose Doxycycline Engineering FDA approved Feedback Fireflies Gene Expression Half-Life Immune response Immune system Immunity Immunologic Surveillance Immunotherapy In Vitro Incidence Injections Interleukin-12 Interleukin-15 Intravenous Kinetics Lesion Link Luciferases Malignant Neoplasms Measurement Messenger RNA Metastatic Neoplasm to the Lung Modeling Mus Neoadjuvant Therapy Neoplasm Metastasis Nonmetastatic Operative Surgical Procedures PD-1 blockade Pathway interactions Patient risk Patients Pharmacodynamics Phase Physiological Population Program Development Recombinant Cytokines Recurrence Regimen Relapse Renilla Reporter Resectable Risk Small Business Innovation Research Grant T cell response T memory cell T-Lymphocyte Testing Therapeutic Time Toxic effect Trimethoprim Tumor Burden United States National Institutes of Health adaptive immune response anti-CTLA4 anti-PD-1 anti-PD-1/PD-L1 anti-PD-L1 therapy anti-PD1 therapy anti-cancer anti-tumor immune response base combat combinatorial cytokine cytokine therapy design high risk immunogenicity immunoregulation improved outcome in vivo innovation lipid nanoparticle lumican mRNA Expression manufacturing process melanoma mouse model nanoparticle delivery novel novel strategies objective response rate pharmacokinetics and pharmacodynamics pre-clinical preclinical study programs prototype relapse risk side effect small molecule standard of care subcutaneous success synthetic biology therapy development tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY While major strides have been made in the development of therapies for melanoma, cases continue to rise, with more diagnoses occurring at an early stage where surgery is indicated for patients. However, even with standard of care anti-PD-1 adjuvant immunotherapy, patients still have a high risk of relapse (3-year relapse-free survival is 50-60%). Neoadjuvant anti-PD-1/anti-CTLA-4 immunotherapy has emerged as a potentially more efficacious alternative to adjuvant immunotherapy, however, widespread usage in these non-metastatic patients would be precluded due to significant toxicities. Therefore, there is a great unmet need to improve outcomes for locally/regionally advanced surgically resectable melanoma patients. Cytokine therapies such as interleukin (IL)- 12 and IL-15 have shown promise in pre-clinical in vitro and in vivo studies, however, when delivered systemically in bolus, their clinical utility is limited due to serious adverse effects as well as suboptimal pharmacokinetics and pharmacodynamics. Thus, we need to find novel ways to locally modulate the immune system early to limit toxicity and reduce the risk of recurrence. To address this challenge in melanoma in this NIH Phase I SBIR, Strand Therapeutics is proposing to engineer a tunable and programmable small molecule-regulated self-replicating mRNA (repRNA)-based combinatorial cytokine immunotherapy that mimics the physiological expression kinetics of IL-12 (expressed early) and IL-15 (expressed later). In doing so, this programmable repRNA immunotherapy is designed to enhance the patient’s own immune system to combat melanoma tumors and provide durable immune surveillance and remission with limited toxicity. In Aim 1, we will construct the mRNA circuit and validate expression kinetics of our programmed mRNAs using surrogate luciferase reporters, which will allow us to assess in vivo expression kinetics in real-time in a mouse model of melanoma. In Aim 2, we will encode IL-12 and IL-15 in the circuit validated in Aim 1 and assess expression kinetics and tunability of IL-12/IL-15 expression in a mouse model of melanoma. In Aim 3, we will test if our engineered circuit can eliminate tumors in vivo in mouse models of melanoma, and benchmark against non- circuit IL-12/IL-15 delivery approaches such as recombinant cytokines and constitutive expression from mRNAs. Successful completion of these studies will lead to a novel programmable circuit with IL-12/IL-15 for the treatment of melanoma. Through this project, we intend to program the natural kinetics of IL-12/IL-15, which will induce stronger and longer-lasting anti-cancer immune responses and increase the efficacy of anti-PD-1/PD-L1 therapies, without the side-effects linked to systemically delivered cytokines.

项目概要尽管黑色素瘤治疗方法的开发取得了重大进展，但病例仍在继续增加，然而，即使有标准，更多的诊断发生在需要手术的早期阶段。尽管接受抗PD-1辅助免疫治疗，患者仍有较高的复发风险（3年无复发生存期）是 50-60%）。新辅助抗 PD-1/抗 CTLA-4 免疫疗法已成为一种潜在更有效的疗法。然而，辅助免疫疗法的替代方案是在这些非转移患者中广泛使用由于显着的毒性而被排除，因此，改善结果的需求非常迫切。局部/区域晚期可手术切除的黑色素瘤患者。细胞因子疗法，例如白细胞介素 (IL)- 然而，当全身给药时，IL-12 和 IL-15 在临床前体外和体内研究中已显示出前景在推注中，由于严重的副作用以及药代动力学欠佳，其临床应用受到限制因此，我们需要找到早期局部调节免疫系统以限制的新方法。为了应对 NIH I 期 SBIR 中黑色素瘤的这一挑战， Strand Therapeutics 提议设计一种可调谐和可编程的小分子调节药物基于自我复制 mRNA (repRNA) 的组合细胞因子免疫疗法，模仿 IL-12（早期表达）和 IL-15（后期表达）的生理表达动力学。可编程repRNA免疫疗法旨在增强患者自身的免疫系统以对抗在目标 1 中，我们将提供持久的免疫监视和缓解以及有限的毒性。构建 mRNA 回路并使用替代物验证我们编程的 mRNA 的表达动力学产生荧光素酶，这将使我们能够在小鼠模型中实时评估体内表达动力学在目标 2 中，我们将在目标 1 中验证的电路中编码 IL-12 和 IL-15 并评估表达。在目标 3 中，我们将测试黑色素瘤小鼠模型中 IL-12/IL-15 表达的动力学和可调性。工程电路可以消除黑色素瘤小鼠模型体内的肿瘤，并与非电路 IL-12/IL-15 递送方法，例如重组细胞因子和 mRNA 的组成型表达。这些研究的成功完成将产生一种用于治疗的新型可编程电路，其中包含 IL-12/IL-15 通过这个项目，我们打算对 IL-12/IL-15 的自然动力学进行编程，这将诱导更强、更持久的抗癌免疫反应，提高抗 PD-1/PD-L1 的功效疗法，没有与全身输送细胞因子相关的副作用。