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确定解决方案。但是，有毒 目前需要化学疗法作为预处理治疗，以损害移植物排斥和维持治疗 血液中的细胞可以靶向癌细胞。化学疗法几乎不受脆弱的癌症的忍受 患者，并促进免疫疗法的副作用，例如有毒细胞因子释放（CRS）和神经疗法。 AVM生物技术（AVM）正在为一种新颖的安全预处理方案而努力，名为AVM0703，该方案 可以轻松施用以提高自适应细胞免疫疗法的有效递送。 AVM0703影响 仅在24小时内安全的淋巴细胞内，少量血小板，干细胞和红细胞。有趣的是，AVM0703 可以安全地复制单核细胞，已知是CRS的关键诱导剂。 CRS毒性频繁发生至90％ 其中一半确定为严重。如果未在 及时的方式。在CRS期间，IL-6的水平升高，动物研究表明单核细胞 是IL-6的主要来源。 IL-6产生单核细胞的耗竭保护了CRS诱导的致死性。 与化学疗法不同，AVM0703可以安全复制单核细胞，以降低CRS的风险并制造细胞 高风险个体（如老年/脆弱患者）可以使用免疫疗法。 AVM0703行动方式可以提供 示例性预处理方案。 为了确定该产品的可行性，我们提出以下两个特定目标。目标1。评估效率 AVM0703作为免疫功能多发性骨髓瘤（MM）小鼠T细胞输血的预处理 模型。淋巴瘤的水平，T细胞循环的改善以及由细胞毒性水平 将监测AVM0703并将其与标准化学疗法进行比较。最后，保证 同种异体T细胞的治疗作用将得到验证。 AIM2。展示了AVM0703和 它可以降低与免疫治疗细胞注射有关的CRS风险的能力。成功 该项目的结果将为使用AVM0703作为预处理药物提供坚实的临床基础 使用当前和未来的自适应细胞疗法，以消除化学疗法的需求。在Sbir期间 第二阶段项目，AVM将与卓越癌症中心合作，以创造新的癌症细胞 基于使用AVM0703来证明其潜在改善临床结果的疗法。最终， AVM0703提供的可容忍的方案可能会破坏未来的“癌症概念”，成为一个简单的慢性 通过反复施用无毒疗法治疗的疾病。