HIFU-immunotherapy in pancreatic cancer

高强度聚焦超声免疫治疗在胰腺癌中的应用 最重要的是，我们发现超声、TLR7/8激动剂与CD40和Checkpoint的结合 抑制(建立在新兴人类研究的方案基础上)有效地消除植入的多部位侵袭 KPC小鼠胰腺肿瘤。最近的研究为激动剂的效用提供了令人信服的证据。 多组分方案治疗胰腺癌中的CD40(ACD40)抗体，以及联合研究 带有检查点调节器和化疗的aCD40已经显示出非常令人鼓舞的数据。表达CD40 在胰腺癌细胞亚群和绝大多数瘤周淋巴细胞上。对于PDAC， ACD40单抗还促进基质降解、树突状细胞成熟和改变。 巨噬细胞表型，因此是一种有吸引力的免疫治疗方法。而NCT03214250 (将吉西他滨和亚伯沙尼与CD40和apd-1免疫疗法相结合)产生了非常有希望的结果 所有接受所有成分治疗的患者都显示转移的胰腺癌T细胞消退 没有观察到激活，患者也没有被治愈。在人类身上可靠地提供这些治疗 胰腺癌具有挑战性，因为它的间质致密，血管供应有限。磁共振的初步研究 引导聚焦超声(MRgFUS)消融人类胰腺肿瘤计划于2020年初开始 在斯坦福大学。在这里，我们将结合MRgFUS和aCD40+检查点抑制策略。我们会立即 如果结果是有希望的，努力转化这样的战略。此外，最近的研究也证明了这一点 类受体(TLR)7/8激动剂具有治疗作用，特别是在胰腺癌中。TLR7/8激动剂是 由于树突状细胞亚群上受体的分布，因此适合翻译。我们的初步数据显示 TLR7/8和aCD40之间的协同作用，我们在AIM中建立在TLR7/8激动剂和aCD40组合的基础上 2.虽然TLR7/8激动剂可以皮内给药，但TLR激动剂直接给药到肿瘤会产生一种 通过将激活的免疫细胞暴露于癌症抗原而促进疗效的原位疫苗接种。我们的预赛 数据表明，用两种治疗方法(静脉注射TLR7/8和CP4)可达到100%的直接治疗 肿瘤和60%的远端KPC肿瘤被消除。人类研究的一个主要挑战是提供 足够数量的抗胰腺癌TLR7/8激动剂和抗体，没有剂量限制性毒性。我们 开发了一种温度敏感型脂质体(TSL)策略，以确保TLR7/8的充分传递 胰腺癌的激动剂，并将此添加到AIM 2中。使用这样的策略，可以提供8%或更多的 对人体肿瘤的注射剂量(至少是免费药物的20倍)，并限制全身毒性。总而言之， 在目标1中，我们将把MRgFUS消融纳入临床相关的aCD40+检查点治疗。在 目的2，我们将在aCD40方案中进一步添加TLR7/8激动剂。作为翻译的额外步骤，我们 将检测原代人胰腺癌细胞TLR7/8和aCD40对增殖的影响。

HIFU-immunotherapy in pancreatic cancer Most importantly, we find that the combination of ultrasound, TLR7/8 agonists with aCD40 and checkpoint inhibition (building on a protocol in emerging human studies) efficiently eliminated implanted multisite invasive KPC murine pancreatic tumors. Recent studies have provided compelling evidence as to the utility of agonist CD40 (aCD40) antibodies within multicomponent protocols to treat pancreatic cancer, and studies combining aCD40 with checkpoint modulators and chemotherapy have shown highly encouraging data. CD40 is expressed on a subset of pancreatic cancer cells and the overwhelming majority of peritumoral lymphocytes. For PDAC, the aCD40 monoclonal antibody also promotes stromal degradation, dendritic cell maturation and alters macrophage phenotype, and therefore is an attractive approach for immunotherapy. While NCT03214250 (combining gemcitabine and Abraxane with aCD40 and aPD-1 immunotherapy) yielded very promising results in which all patients receiving all components demonstrated regression of metastatic pancreatic cancer, T cell activation was not observed and patients were not cured. Reliably delivering these treatments in human pancreatic cancer is challenging due to the dense stroma and limited vascular supply. Initial studies of MR guided focused ultrasound (MRgFUS) to ablate human pancreatic tumors are scheduled to begin in early 2020 at Stanford. Here, we will combine MRgFUS with an aCD40+checkpoint inhibitor strategy. We will immediately work to translate such a strategy if results are promising. Further, recent work has also demonstrated that toll like receptor (TLR)7/8 agonists have therapeutic utility, particularly in pancreatic cancer. TLR7/8 agonists are desirable for translation due to the distribution of receptors on subsets of DCs. Our preliminary data demonstrate synergy between TLR7/8 and aCD40, and we build on the combination of TLR7/8 agonists and aCD40 in Aim 2. While TLR7/8 agonists can be delivered intradermally, the direct delivery of TLR agonists to tumors yields an in situ vaccination that facilitates efficacy by exposing activated immune cells to cancer antigen. Our preliminary data indicate that with 2 treatments (with intravenous injection of TLR7/8 and CP4) up to 100% of directly-treated tumors and 60% of distant KPC tumors were eliminated. A major challenge for human studies is to deliver sufficient quantities of TLR7/8 agonists and antibodies to pancreatic cancer without dose-limiting toxicity. We have developed a temperature-sensitive liposomal (TSL) strategy to assure adequate delivery of TLR7/8 agonists to pancreatic cancer and add this in Aim 2. With such a strategy, it is feasible to deliver 8% or more of the injected dose to a human tumor (at least 20 fold more than free drug) and limit systemic toxicity. In summary, within Aim 1, we will incorporate MRgFUS ablation into clinically-relevant aCD40+checkpoint therapy. Within Aim 2, we will further add TLR7/8 agonists to an aCD40 protocol. As an additional step toward translation, we will assay primary human pancreatic cancer cells as to the effect of TLR7/8 and aCD40 on proliferation.