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

在美国，胰腺导管腺癌是导致癌症死亡的第三大常见原因。 令人沮丧的5年总体存活率为9%的州。手术治疗是目前治疗PDAC的唯一方法， 然而，80%的患者在就诊时由于局部晚期和/或转移而被认为不能切除。 疾病。现有的治疗方法通常不能缩小局部晚期PDAC(LAPC)的手术候选范围， 并且在提供远端肿瘤控制方面也是无效的。两种局部治疗方法都能 降低分期和控制复发/转移肿瘤是提高切除率的迫切需要。这 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得到满足的需求 并探索其对人类LAPC的影响。我们最近发表的研究表明，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聚焦到 肿瘤，结合聚合物包裹的强大的免疫细胞刺激细胞因子白介素12(IL-12) 在临床前模型中，微球(IL-12MS)具有显著的肿瘤控制和持久治愈作用。 微球技术代表了一种创新的工具，它提供了缓慢、连续的细胞因子释放 同时保护不稳定的IL-12蛋白不被蛋白酶降解。这两种技术的结合 使用IL-12MS的SBRT不仅强烈刺激包括细胞毒T细胞在内的免疫系统的适应性臂 细胞破坏胰腺肿瘤细胞，也对细胞的先天免疫系统有复极化作用 将典型的免疫抑制髓系细胞转化为具有免疫刺激潜力的细胞。把这个搬到 我们假设SBRT/IL-12MS联合治疗是安全的和 可耐受，并将改善无进展生存率和肿瘤降期，使手术切除成为可能 LAPC。在目标1中，我们将建立一项临床试验，探索SBRT在人类中的第一次使用，然后是超声波- IL-12MS在不能切除的LAPC患者中的应用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 外周血研究以及从登记患者收集的基线和研究中的肿瘤活检。 这些数据将解决SBRT/IL-12MS是否会使肿瘤微环境(TME)从 从免疫“冷”瘤到免疫“热”瘤。目标3将利用临床前建模来 开发一种使用SBRT/IL-12MS治疗转移性PDAC的策略。这些结果在顺序上是必不可少的 将这种疗法推广到几乎没有有效治疗方法的转移性患者。总的来说，我们的 拟议的应用建立在前景看好的临床前数据的基础上，显示了SBRT/IL-1联合治疗的潜在疗效。 12MS治疗LAPC/转移性病变。这一技术创新战略利用了一种独特的 重新极化TME的策略来治疗这种几乎没有有效治疗方法的顽固性恶性肿瘤。

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.