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: 10278557
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10278557
• 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; Ultrasonography; 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; peripheral blood; pre-clinical; protein degradation; response; success; systemic toxicity; tool; treatment optimization; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions

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.

胰腺导管腺癌癌（PDAC）是联合癌症死亡的第三大原因 5年总生存期9％的州惨淡的州。手术干预目前是PDAC的唯一治疗方法 但是，由于局部晚期和/或转移性，有80％的患者被认为是无法切除的。 疾病。现有疗法通常无法缩小本地高级PDAC（LAPC）的尺寸 并且在提供远端肿瘤控制方面也无效。治疗方法使两者都可以 迫切需要降低和复发/转移性肿瘤控制以提高切除率。这 应用将通过将创新组合免疫疗法转换为诊所，以满足未满足的需求 并探索其对人类LAPC的影响。我们最近发表的工作表明了立体定向的身体 放射治疗（SBRT），一种毒性较小，更有效的策略，将更高剂量辐射的重点恰好精确地放在 肿瘤，结合封装在聚合物中 微球（IL-12ms）在临床前模型中导致明显的肿瘤控制和耐用的治疗。 微球技术代表了一种创新的工具，可提供细胞因子的缓慢，连续释放 肿瘤内，同时还保护不稳定的IL-12蛋白免受蛋白酶降解。结合 具有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，但对先天免疫系统细胞具有复极作用 通常将免疫抑制性髓样细胞转化为具有免疫刺激潜力的细胞。移动这个 有前途的疗法进入诊所，我们假设SBRT/IL-12MS疗法组合是安全的，并且 可以容忍的，并将改善无进度的生存和肿瘤下降以使切除 LAPC。在AIM 1中，我们将建立一项临床试验，探讨SBRT的第一次人类使用，然后进行超声波检查 无法切除的LAPC患者的IL-12MS递送。主要目的是评估安全性和 耐受性和次要目标是评估效率和总体结果。 AIM 2将进行推论 从研究患者收集的有关外周血以及基线和研究的肿瘤活检的研究。 这些数据将解决SBRT/IL-12MS是否从A的肿瘤微环境（TME）重现 在免疫学上“冷”肿瘤是免疫学上“热”的肿瘤。 AIM 3将利用临床前建模 开发一种使用SBRT/IL-12MS治疗治疗转移性PDAC的策略。这些结果至关重要 将这种疗法扩展到几乎没有有效治疗的转移患者中。总体而言，我们的 拟议的应用基于承诺的临床前数据，显示了联合SBRT/IL-的潜在有效性 12ms的LAPC/转移性病变患者的治疗。这种技术创新的策略利用了独特的 将TME重新极化的策略以治疗这种顽固性恶性肿瘤，几乎没有有效的疗法。