HIFU-immunotherapy in pancreatic cancer

胰腺癌的 HIFU 免疫治疗

• 批准号: 10425306
• 负责人: Katherine W Ferrara
• 金额: $ 61.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425306
• 关键词: Ablation; Abraxane; Address; Agonist; Animals; Antibodies; Antibody Therapy; Biological Assay; Cell Maturation; Cell model; Cells; Characteristics; Clinical Research; Combination immunotherapy; Data; Dendritic Cells; Distant; Dose; Dose-Limiting; Ensure; Flow Cytometry; Focused Ultrasound; Focused Ultrasound Therapy; Future; Head and Neck Cancer; Human; Hyperthermia; Immune; Immune checkpoint inhibitor; Immune response; Immunotherapy; Implant; KPC model; Liposomes; Lymphocyte; Lymphoma; Magnetic Resonance; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Molecular; Monitor; Monoclonal Antibodies; Mus; Myeloid-derived suppressor cells; Pancreas; Pancreatic Ductal Adenocarcinoma; Patients; Penetration; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Protocols documentation; Regulatory T-Lymphocyte; Safety; Schedule; Site; T-Cell Activation; T-cell inflamed; TLR7 gene; TNFRSF5 gene; Temperature; Testing; Therapeutic; Toll-like receptors; Toxic effect; Translating; Translations; Treatment Protocols; Tumor Antigens; Tumor Volume; Vascular blood supply; Work; anti-CTLA4; anti-PD-1; base; checkpoint inhibition; checkpoint therapy; chemotherapy; clinically relevant; cohort; gastrointestinal; gemcitabine; imaging modality; imaging probe; improved; in situ vaccination; intravenous injection; macrophage; malignant breast neoplasm; mouse model; neoplastic cell; pancreatic cancer cells; pancreatic cancer model; pancreatic neoplasm; patient derived xenograft model; porcine model; receptor; resiquimod; response; single cell analysis; synergism; systemic toxicity; transcriptome sequencing; tumor; ultrasound; ultrasound ablation

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.

胰腺癌的 HIFU 免疫治疗 最重要的是，我们发现超声、TLR7/8 激动剂与 aCD40 和检查点的组合 抑制（建立在新兴人类研究方案的基础上）有效地消除了植入的多部位侵入性 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 用于治疗胰腺癌的多组分方案中的 CD40 (aCD40) 抗体以及结合的研究 aCD40 与检查点调节剂和化疗已显示出非常令人鼓舞的数据。 CD40表达 对胰腺癌细胞的子集和绝大多数瘤周淋巴细胞。对于 PDAC， aCD40 单克隆抗体还促进基质降解、树突状细胞成熟并改变 巨噬细胞表型，因此是免疫治疗的一种有吸引力的方法。而NCT03214250 （将吉西他滨和 Abraxane 与 aCD40 和 aPD-1 免疫疗法相结合）产生了非常有希望的结果 其中接受所有成分的所有患者均表现出转移性胰腺癌、T 细胞的消退 没有观察到激活，患者也没有治愈。在人体中可靠地提供这些治疗 由于间质致密和血管供应有限，胰腺癌具有挑战性。 MR的初步研究 用于消融人类胰腺肿瘤的引导聚焦超声 (MRgFUS) 计划于 2020 年初开始 在斯坦福大学。在这里，我们将 MRgFUS 与 aCD40+ 检查点抑制剂策略结合起来。我们将立即 如果结果有希望，就努力转化这样的战略。此外，最近的工作还表明，收费 样受体 (TLR)7/8 激动剂具有治疗效用，特别是在胰腺癌中。 TLR7/8 激动剂是 由于受体分布在 DC 子集上，因此对于翻译来说是理想的。我们的初步数据表明 TLR7/8 和 aCD40 之间的协同作用，我们在 Aim 中以 TLR7/8 激动剂和 aCD40 的组合为基础 2. 虽然 TLR7/8 激动剂可以皮内递送，但将 TLR 激动剂直接递送至肿瘤会产生 原位疫苗接种通过将激活的免疫细胞暴露于癌症抗原来提高疗效。我们的初步 数据表明，2次治疗（静脉注射TLR7/8和CP4）高达直接治疗的100% 肿瘤和 60% 的远处 KPC 肿瘤被消除。人类研究的一个主要挑战是提供 足量的 TLR7/8 激动剂和胰腺癌抗体，无剂量限制性毒性。我们 开发了温度敏感脂质体 (TSL) 策略以确保 TLR7/8 的充分递送 胰腺癌激动剂并将其添加到目标 2 中。采用这样的策略，可以实现 8% 或更多的 人类肿瘤的注射剂量（至少是游离药物的 20 倍）并限制全身毒性。总之， 在目标 1 中，我们将把 MRgFUS 消融纳入临床相关的 aCD40+检查点治疗中。之内 目标 2，我们将进一步将 TLR7/8 激动剂添加到 aCD40 方案中。作为翻译的额外一步，我们 将检测原代人胰腺癌细胞 TLR7/8 和 aCD40 对增殖的影响。