Repolarizing the Tumor and Metastatic Microenvironments to Treat Patients with Pancreatic Cancer

重新极化肿瘤和转移性微环境来治疗胰腺癌患者

• 批准号: 10460543
• 负责人: Scott Andrew Gerber
• 金额: $ 51.6万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460543
• 关键词: Address; Biopsy; Blood specimen; CD8-Positive T-Lymphocytes; Cancer Etiology; Cancer Model; Cells; Cessation of life; Clinic; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Diagnosis; Disease; Distal; Encapsulated; Enrollment; Excision; Exhibits; Future; Genetically Engineered Mouse; Human; Immune; Immune response; Immune system; Immunologics; Immunotherapeutic agent; Immunotherapy; Injections; Innate Immune System; Innovative Therapy; Interferon Type II; Interleukin-12; Lead; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Liver; Metastatic/Recurrent; Microspheres; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Peptide Hydrolases; Pharmacologic Substance; Polymers; Pre-Clinical Model; Primary Neoplasm; Production; Prognosis; Progression-Free Survivals; Publishing; Radiation Dose Unit; Radiation therapy; Research Personnel; Resectable; Safety; Sampling; Schedule; Technology; Testing; Therapeutic; Therapeutic Effect; Translating; United States; Unresectable; Work; adaptive immune response; advanced pancreatic cancer; arm; bench to bedside; cancer type; clinical application; clinically relevant; cytokine; effective therapy; effector T cell; efficacy evaluation; first-in-human; immunoregulation; improved; innovation; irradiation; multiple sclerosis treatment; novel; pancreatic cancer cells; pancreatic cancer patients; pancreatic neoplasm; patient prognosis; peripheral blood; pre-clinical; protein degradation; response; success; systemic toxicity; tool; treatment optimization; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions; ultrasound

Pancreatic ductal adenocarcinoma cancer (PDAC) is the 3rd most common cause of cancer deaths in the United States with a dismal 5-year overall survival of 9%. Surgical intervention is currently the only cure for PDAC, however, 80% of patients are deemed unresectable at presentation due to locally advanced and/or metastatic disease. Existing therapies are often unable to downsize locally advanced PDAC (LAPC) for surgical candidacy, and are also ineffective at providing distal tumor control. Therapeutic approaches capable of both local downstaging and recurrent/metastatic tumor control are desperately needed to improve resectability rates. This application will address the unmet need by translating an innovative combination immunotherapy to the clinic and exploring its effects on LAPC in humans. Our recently published work demonstrated that stereotactic body radiotherapy (SBRT), a less toxic, more effective strategy that focuses higher dose radiation precisely to the tumor, combined with the potent immune cell–stimulating cytokine interleukin-12 (IL-12) encapsulated in polymer microspheres (IL-12MS) resulted in remarkable tumor control and durable cure in preclinical models. Microsphere technology represents an innovative tool that provides a slow, continuous release of cytokine intratumorally while also protecting the labile IL-12 protein from degradation by proteases. The combination of SBRT with IL-12MS not only strongly stimulated the adaptive arm of the immune system including cytotoxic T cells to destroy pancreatic tumor cells, but also had a repolarizing effect on cells of innate immune system converting typically immunosuppressive myeloid cells into ones with immunostimulatory potential. Moving this promising therapy into the clinic, we hypothesize that combined SBRT/IL-12MS therapy is safe and tolerable, and will improve progression-free survival and tumor downstaging to enable resection in LAPC. In Aim 1, we will establish a clinical trial exploring the first-in-human use of SBRT followed by ultrasound- guided IL-12MS delivery in patients with unresectable LAPC. The main objective is to evaluate safety and tolerability, and the secondary objective is to evaluate efficacy and overall outcome. Aim 2 will perform corollary studies on peripheral blood along with baseline and on-study tumor biopsies collected from enrolled patients. These data will address whether SBRT/IL-12MS repolarizes the tumor microenvironment (TME) from an immunologically “cold” tumor to one that is immunologically “hot”. Aim 3 will utilize preclinical modelling to develop a strategy to treat metastatic PDAC using SBRT/IL-12MS therapy. These results are essential in order to expand this therapy into metastatic patients where there are little to no effective treatments. Overall, our proposed application builds on promising preclinical data showing the potential efficacy of combined SBRT/IL- 12MS therapy for patients with LAPC/metastatic lesions. This technologically innovative strategy utilizes a unique strategy of repolarizing the TME to treat this recalcitrant malignancy for which there are few effective therapies.

胰腺导管腺癌 (PDAC) 是美国第三大癌症死亡原因 5 年总生存率仅为 9% 的国家。手术干预是目前治疗 PDAC 的唯一方法， 然而，80% 的患者因局部晚期和/或转移性病变而被认为无法切除 疾病。现有疗法通常无法缩小局部晚期 PDAC (LAPC) 的手术候选范围， 并且在提供远端肿瘤控制方面也无效。能够局部治疗的方法 迫切需要降期和复发/转移肿瘤控制来提高可切除率。这 该应用程序将通过将创新的联合免疫疗法转化为临床来解决未满足的需求 并探索其对人类 LAPC 的影响。我们最近发表的工作表明，立体定向体 放射治疗 (SBRT)，一种毒性更小、更有效的策略，可将更高剂量的辐射精确地集中到目标部位 与封装在聚合物中的强效免疫细胞刺激细胞因子白细胞介素 12 (IL-12) 相结合 微球（IL-12MS）在临床前模型中产生了显着的肿瘤控制和持久治愈效果。 微球技术代表了一种创新工具，可以缓慢、持续地释放细胞因子 瘤内，同时还保护不稳定的 IL-12 蛋白免遭蛋白酶降解。的组合 使用 IL-12MS 的 SBRT 不仅强烈刺激免疫系统的适应性臂，包括细胞毒性 T 细胞破坏胰腺肿瘤细胞，但也对先天免疫系统细胞具有复极化作用 将典型的免疫抑制性骨髓细胞转化为具有免疫刺激潜力的细胞。移动这个 由于该疗法有望进入临床，我们假设 SBRT/IL-12MS 联合疗法是安全且有效的 可以耐受，并将提高无进展生存率和肿瘤降期，从而实现切除 洛杉矶PC。在目标 1 中，我们将建立一项临床试验，探索首次在人体中使用 SBRT，然后进行超声治疗。 引导 IL-12MS 递送至不可切除的 LAPC 患者。主要目标是评估安全性和 耐受性，次要目标是评估疗效和总体结果。目标 2 将执行推论 对外周血以及从入组患者收集的基线和研究中肿瘤活检进行的研究。 这些数据将解决 SBRT/IL-12MS 是否使肿瘤微环境 (TME) 从 免疫学上的“冷”肿瘤与免疫学上的“热”肿瘤。目标 3 将利用临床前建模 制定使用 SBRT/IL-12MS 疗法治疗转移性 PDAC 的策略。这些结果对于顺序至关重要 将这种疗法扩展到几乎没有有效治疗方法的转移性患者。总体而言，我们的 拟议的应用建立在有希望的临床前数据的基础上，这些数据显示了 SBRT/IL 组合的潜在功效 LAPC/转移性病变患者的 12MS 治疗。这一技术创新策略利用了独特的 重新极化 TME 来治疗这种顽固性恶性肿瘤的策略是有效的治疗方法很少。