Building a New Therapeutic Paradigm for Hepatocellular Cancer by Dissecting the Interaction between Radiofrequency Ablation, Chemotherapy, and Immunotherapy

通过剖析射频消融、化疗和免疫疗法之间的相互作用，建立肝细胞癌的新治疗范式

• 批准号: 10265346
• 负责人: Eric T. Kimchi
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265346
• 关键词: Ablation; Animal Model; Antibodies; Antigens; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Control; Cancer Etiology; Cancer Patient; Cardiac; Clinical; Combined Modality Therapy; Development; Disease; Electrodes; Elements; FDA approved; Family; Frequencies; Funding; General Population; Goals; Hepatocyte transplantation; Histologic; Hospitalization; Human; Image; Imaging technology; Immune Tolerance; Immune checkpoint inhibitor; Immune response; Immuno-Chemotherapy; Immunocompetent; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Situ; Incidence; Inferior; Life Style; Ligands; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Mediating; Modality; Modeling; Modernization; Morbidity - disease rate; Mus; Myeloid-derived suppressor cells; N-caproylsphingosine; Nanotechnology; Needles; Outcome; PD-1 blockade; Pathway interactions; Patients; Phase; Physiological; Primary carcinoma of the liver cells; Protocols documentation; Radiofrequency Interstitial Ablation; Recurrence; Regulatory T-Lymphocyte; Research Personnel; Risk Factors; Role; Safety; Small Business Innovation Research Grant; Solid Neoplasm; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Translating; Tumor Antigens; Tumor Immunity; Tumor Suppression; Tumor-associated macrophages; United States National Institutes of Health; Up-Regulation; Veterans; Visualization; Wild Type Mouse; Work; anti-PD-1; anti-tumor immune response; base; cancer immunotherapy; cancer initiation; cancer therapy; cancer type; checkpoint therapy; chemotherapeutic agent; chemotherapy; clinical application; clinical practice; clinically relevant; cost; design; exhaustion; image guided; immune checkpoint; immune resistance; immunoreaction; improved; innovation; insight; military service; mortality; mouse model; nanoliposome; neoplastic; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; overexpression; preclinical study; prevent; programmed cell death ligand 1; programmed cell death protein 1; receptor; response; service member; therapeutic evaluation; treatment strategy; tumor; tumor ablation; tumor growth; tumor microenvironment; tumor progression

Hepatocellular cancer (HCC) remains one of the deadliest cancers with limited clinical options. Due of life style choices, living conditions, and/or environmental elements, risk factors for the development of HCC cause the increased incidence in military service members, veterans, and their families with 10-fold higher than the general population. Radiofrequency ablation (RFA) has emerged as a first line treatment option for patients with HCC. When combined with modern imaging, RFA can be performed percutaneously or laparoscopically. Image-guided RFA has the following significant advantages: lower morbidity, minimized physiologic insult of surrounding tissues, reduced cost, short hospitalization time, and intra-procedural visualization for precise targeting. However, incomplete ablation, tumor recurrence, and inferior outcomes persist, revealing that rational combination with other therapeutic strategies is needed to more effectively treat HCC. Breakthroughs in cancer immunotherapy offer potential promise for HCC treatment, but no approaches have been translated into clinical application. In situ RFA capably destroys tumor cells to release substantial antigens that might modulate antitumor immunity. However, the resultant therapeutic immune response by RFA alone is too modest to destroy established tumors. This is because tumors develop different mechanisms to induce profound immunotolerance in the tumor microenvironment. Therefore, overcoming tumor-induced immunotolerance is critically important for RFA-liberated antigens to prime powerful antitumor immune response. Recently, the investigators created a novel murine model. This model mimics human HCC initiation and progression, and reflects typical features of human HCC including tumor-induced immunotolerance. Using this model, they have first demonstrated that FDA-approved chemotherapeutic agent, sunitinib, prevents tumor antigen-specific immunotolerance and allows effective immunotherapy resulting in regression of established tumors in HCC, which is mechanistically associated with suppression of Tregs. By using nanotechnology to develop nanoliposome-loaded C6-ceramide (LipC6), they demonstrated that LipC6 not only exerts tumoricidal effect but also prevents tumor-induced immunotolerance by modulating tumor-associated macrophages (TAMs). They have also found a critical role of immune checkpoints in HCC-induced profound immunosuppression, and demonstrated that Ab-mediated blockade of PD-1 has a significant immunotherapeutic effect in the experimental- HCC treatment. In addition, the investigators have successfully modified a human cardiac RFA generator, and they are now able to conduct HCC tumor ablations in this novel murine model. The overall objective of the proposed study is to develop and define the mechanisms of RFA-integrated chemo-immunotherapy against HCC. They will achieve this goal via two specific aims: 1) Determine the therapeutic antitumor immune response and elucidate the underlying mechanisms in tumor bearing mice treated with sunitinib, LipC6, RFA, and their combination; 2) Determine the dominant inhibitory immune checkpoint pathways mediating immune resistance in HCC and develop a rational combination therapy with RFA for HCC control. Completion of the proposed study is expected to generate new and clinically feasible therapeutic strategies which can be translated into clinical practice for the treatment of this deadly cancer.

肝细胞癌（HCC）仍然是最致命的癌症之一，临床选择有限。稿上交截止日 生活方式选择、生活条件和/或环境因素、HCC发展的风险因素 导致军人、退伍军人及其家属的发病率增加， 普通民众。射频消融（RFA）已成为患者的一线治疗选择 与HCC当与现代成像技术相结合时，RFA可以在经皮或腹腔镜下进行。 图像引导射频消融具有以下显着优势：发病率较低，最大限度地减少生理损伤 周围组织，降低成本，缩短住院时间，术中可视化， 面向.然而，不完全消融、肿瘤复发和较差的结果仍然存在，这表明合理的消融治疗是可行的。 需要与其他治疗策略组合以更有效地治疗HCC。 癌症免疫治疗的突破为肝癌治疗提供了潜在的希望，但没有方法 已经转化为临床应用。原位RFA能够破坏肿瘤细胞，释放大量的 可能调节抗肿瘤免疫的抗原。然而，RFA产生的治疗性免疫应答 单独使用过于温和，无法摧毁已形成的肿瘤。这是因为肿瘤发展了不同的机制， 在肿瘤微环境中诱导深刻的免疫耐受。因此，克服肿瘤诱导的 免疫耐受性对于RFA释放的抗原引发强大的抗肿瘤免疫应答至关重要。 最近，研究人员创造了一种新的小鼠模型。该模型模拟人HCC起始， 进展，并反映了人HCC的典型特征，包括肿瘤诱导的免疫耐受。使用此 他们首次证明FDA批准的化疗药物舒尼替尼可以预防肿瘤， 抗原特异性免疫耐受，并允许有效的免疫治疗，导致建立的免疫耐受的消退。 HCC中的肿瘤，其在机制上与抑制TcB相关。通过使用纳米技术 开发了纳米脂质体负载的C6-神经酰胺（LipC 6），他们证明LipC 6不仅具有杀肿瘤作用， 这种免疫耐受性不仅可以抑制肿瘤诱导的免疫耐受性，而且还可以通过调节肿瘤相关巨噬细胞（TAM）来预防肿瘤诱导的免疫耐受性。 他们还发现了免疫检查点在HCC诱导的严重免疫抑制中的关键作用， 表明Ab介导的PD-1阻断在实验中具有显著的免疫抑制作用， 肝癌治疗。此外，研究人员还成功地改造了人体心脏RFA发生器， 他们现在能够在这种新的小鼠模型中进行HCC肿瘤消融。的总体目标 拟议的研究是开发和定义RFA整合化学免疫疗法的机制， HCC。他们将通过两个具体目标实现这一目标：1）确定治疗性抗肿瘤免疫应答 并阐明了舒尼替尼、LipC 6、RFA治疗荷瘤小鼠的潜在机制， 2）确定介导免疫抗性的显性抑制性免疫检查点途径 探讨射频消融联合治疗肝癌合理性。 完成拟议的研究，预计将产生新的和临床可行的治疗 这些策略可以转化为治疗这种致命癌症的临床实践。