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

胰腺导管腺癌（PDAC）是美国癌症死亡的第三大常见原因。 5年总生存率为9%。手术干预是目前唯一治愈PDAC的方法， 然而，由于局部晚期和/或转移性肿瘤，80%的患者在就诊时被认为是不可切除的。 疾病现有疗法通常无法缩小局部晚期PDAC（LAPC）的手术候选资格， 并且也不能有效地提供远端肿瘤控制。治疗方法既能局部 迫切需要降低分期和复发/转移肿瘤控制以提高可切除率。这 该应用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），一种毒性较小，更有效的策略，将更高剂量的辐射精确地集中在 肿瘤，与包封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）结合 微球（IL-12 MS）在临床前模型中导致显著的肿瘤控制和持久的治愈。 微球技术代表了一种创新的工具，提供了一个缓慢的，连续的释放细胞因子 同时还保护不稳定的IL-12蛋白免于被蛋白酶降解。的组合 使用IL-12 MS的SBRT不仅强烈刺激了免疫系统的适应性臂，包括细胞毒性T细胞， 细胞摧毁胰腺肿瘤细胞，但也对先天免疫系统的细胞有复极化作用 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骨髓细胞。提出这项 有希望的治疗进入临床，我们假设联合SBRT/IL-12 MS治疗是安全的， 可耐受，并将改善无进展生存期和肿瘤降级， LAPC。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，然后使用超声- 在患有不可切除LAPC的患者中引导IL-12 MS递送。主要目的是评估安全性， 耐受性，次要目的是评价疗效和总体结局。目标2将执行推论 外周血沿着研究以及从入组患者中采集的基线和研究期间肿瘤活检。 这些数据将解决SBRT/IL-12 MS是否使肿瘤微环境（TME）从肿瘤微环境（TME）的极化恢复。 从免疫学上的“冷”肿瘤到免疫学上的“热”肿瘤。Aim 3将利用临床前建模， 开发使用SBRT/IL-12 MS疗法治疗转移性PDAC的策略。这些结果对于 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 提出的应用建立在有希望的临床前数据的基础上，这些数据显示了联合SBRT/IL- LAPC/转移性病变患者的12 MS治疗。这一技术创新战略利用了独特的 策略的复极化TME治疗这种复发性恶性肿瘤，有几个有效的疗法。

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.