A novel non-toxic preconditioning regimen for cancer cell therapy

一种用于癌细胞治疗的新型无毒预处理方案

• 批准号: 10011600
• 负责人: Theresa Deisher
• 金额: $ 22.48万
• 依托单位: AVM BIOTECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011600
• 关键词: Address; Adoptive Cell Transfers; Adoptive Immunotherapy; Adrenal Cortex Hormones; Allogenic; Animals; Autologous; Biotechnology; Blood Circulation; Blood Platelets; Blood specimen; Body Weight decreased; Cancer Center; Cancer Model; Cancer Patient; Caring; Cell Therapy; Cells; Cellular immunotherapy; Chronic Disease; Cities; Clinical; Complete Blood Count; Development; Dexamethasone; Diffusion; Dose; Engraftment; Erythrocytes; Excipients; Flow Cytometry; Formulation; Foundations; Future; Generations; Graft Rejection; Half-Life; Health; Hospitalization; Hour; Human; Immune system; Immunocompetent; Immunohistochemistry; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; Improve Access; Individual; Infusion procedures; Injections; Interleukin-2; Interleukin-6; Life; Lymphatic; Malignant Neoplasms; Mediating; Medical; Medical Care Costs; Modeling; Monitor; Multiple Myeloma; Mus; Names; Oral; Outcome; Patients; Pharmaceutical Preparations; Phase; Placebos; Plasma; Rattus; Regenerative Medicine; Regimen; Risk; Safety; Savings; Site; Small Business Innovation Research Grant; Solid; Source; Spleen; System; T-Lymphocyte; Technology; Therapeutic; Therapeutic Effect; Time; Toxic effect; Transfusion; Treatment-related toxicity; Validation; Vertebral column; cancer cell; cancer immunotherapy; cancer therapy; cancer type; chemotherapeutic agent; chemotherapy; clinical practice; cytokine; cytokine release syndrome; cytotoxicity; design; experience; flu; high risk; improved; monocyte; mouse model; novel; pre-clinical; preconditioning; prevent; receptor; side effect; stem cells; tumor

PROJECT SUMMARY Cellular immunotherapy has the potential to become the definitive solution for cancer. However, toxic chemotherapy is currently required as preconditioning treatment to impair graft rejection and maintain therapeutic cells in the bloodstream where they can target cancer cells. Chemotherapy is hardly tolerated by frail cancer patients, and it fuels the side effects of immunotherapy such as toxic cytokine releases (CRS) and neuroedemas. AVM Biotechnology (AVM) is working towards a novel safe pre-conditioning regimen, named AVM0703, which could be easily administered to increase efficient delivery of adoptive cellular immunotherapy. AVM0703 induces safe lymphodepletion in only 24 hours, sparing platelets, stem cells and red blood cells. Interestingly, AVM0703 can safely deplete monocytes, known to be a key inducer of CRS. CRS toxicities occur as frequently as 90% with half of them determined as severe. Severe CRS complications can be life threatening if not treated in a timely manner. Levels of IL-6 are elevated during CRS and animal studies have demonstrated that monocytes are the primary source of IL-6. Depletion of IL-6 producing monocytes protected mice from CRS-induced lethality. Unlike chemotherapy, AVM0703 can safely deplete monocytes reducing the risk of CRS and making cellular immunotherapy accessible to high-risk individuals like older/frail patients. AVM0703 mode of action could offer an exemplary preconditioning regimen. To establish feasibility for this product, we propose the following two specific aims. Aim 1. Evaluate the efficacy of AVM0703 as preconditioning for T-cell transfusion in an immunocompetent Multiple Myeloma (MM) mouse model. The level of lymphodepletion, improvement in T cell circulation, and the level of cytotoxicity induced by AVM0703 will be monitored and compared to standard chemotherapy. Finally, the ability to guarantee the therapeutic effect of allogeneic T-cells will be validated. Aim2. Demonstrate improved safety of AVM0703 and its ability to decrease risks of CRS associated with the injection of immunotherapeutic cells. The successful outcome of this project will provide the solid clinical foundation for the use of AVM0703 as preconditioning drug with current and future adoptive cellular therapies, to remove the need for chemotherapy. During an SBIR Phase II project, AVM will collaborate with Cancer Centers of Excellence for the generation of novel cancer cell therapies based on the use of AVM0703 to demonstrate their potential improved clinical outcomes. Ultimately, the tolerable regimen offered by AVM0703 might disrupt the future “cancer concept” becoming a simple chronic disease treated with repeated administrations of non-toxic therapies.

项目摘要 细胞免疫疗法有可能成为癌症的最终解决方案。然而，有毒 目前需要化疗作为预处理以削弱移植物排斥反应并维持治疗性排斥反应。 在血液中的细胞，他们可以靶向癌细胞。虚弱的癌症患者很难耐受化疗 它加剧了免疫治疗的副作用，如毒性细胞因子释放（CRS）和神经水肿。 AVM生物技术（AVM）正在致力于开发一种新的安全预处理方案，名为AVM0703， 可以容易地施用以增加过继细胞免疫疗法的有效递送。AVM0703诱导 仅在24小时内安全清除淋巴细胞，保留血小板，干细胞和红细胞。AVM0703 可以安全地消耗单核细胞，已知单核细胞是CRS的关键诱导物。CRS毒性的发生频率高达90% 其中一半被确定为严重。严重的CRS并发症如果不及时治疗可能危及生命。 适时CRS期间IL-6水平升高，动物研究表明单核细胞 是IL-6的主要来源。产生IL-6的单核细胞的消耗保护小鼠免于CRS诱导的致死。 与化疗不同，AVM0703可以安全地消耗单核细胞，降低CRS的风险，并使细胞增殖减少。 免疫疗法可用于高风险个体，如老年人/体弱患者。AVM0703的作用方式可以提供 示例性预处理方案。 为了确定该产品的可行性，我们提出了以下两个具体目标。目标1.评定疗效 AVM0703作为免疫活性多发性骨髓瘤（MM）小鼠T细胞输注的预处理 模型淋巴细胞耗竭水平、T细胞循环改善和由 将监测AVM0703并与标准化疗进行比较。最后，保障能力 将验证同种异体T细胞的治疗效果。目标2。证明AVM0703的安全性提高， 它能够降低与注射免疫细胞相关的CRS风险。成功 本课题的研究结果将为AVM0703作为预处理药物的应用提供坚实的临床基础 与当前和未来的过继细胞疗法，以消除对化疗的需要。在SBIR期间 第二阶段项目，AVM将与癌症卓越中心合作，产生新的癌细胞 基于使用AVM0703的治疗，以证明其潜在的改善临床结局。最后， AVM0703提供的可耐受方案可能会破坏未来的"癌症概念"，使其成为一种简单的慢性病， 通过反复给予无毒治疗治疗的疾病。