Stimulating Lymphocyte Activation Combined with Inhibition of Immunosuppressive Signals in Colon Cancer Metastases

项目摘要/摘要 结肠癌和结直肠癌肝转移(CRLM)是一种重要且日益致命的疾病。尽管 利用免疫系统治疗这种癌症有很强的科学前提，仍然有一个基础- 对免疫疗法如何用于大多数此类肿瘤的理解存在心理差距，特别是- 大的微卫星稳定的癌症。中心假设是肿瘤微环境是可以操纵的-- 以增强细胞毒性淋巴细胞的渗透和激活，这种检查点阻断可以同时进行 被用来激发临床相关的免疫反应。这一“一击两拳”的假说 基于申请人提供的初步数据，其中增加对TU-T细胞的贩运- MORS联合CTLA4阻断可导致CRLM完全消退。该计划的基本原理 拟议的研究是，一旦知道如何在微环境中增强免疫刺激信号 在抑制抑制作用的同时，治疗结肠癌的新策略是POS。 有可能。在基于发表的论文和可靠的初步数据的非常强大的科学前提的支持下， 这一假说将通过追求三个具体目标来检验：1)确定增强淋巴转移的机制。 免疫抑制对结肠癌细胞增殖和抗肿瘤特异性免疫反应的影响 传递信号，2)检查直接向肿瘤提供免疫刺激影响的机制；以及3) 将检查点封锁与选择性人光传输相结合，治疗手术切除的肿瘤和 临床前自体系统中的人CRLM。在第一个目标下，我们希望增加淋巴细胞的浸润率- 在抑制免疫抑制信号/细胞的同时抑制微血管内的免疫抑制信号/细胞 使用申请者建立的经过验证的临床前模型的环境。在第二个目标中，临床上 使用新的肿瘤特异性基因安全增加结肠癌肿瘤内LIGH表达的相关方法 将对申请者设计的病毒传递机制进行分析。在第三个目标下，患者肿瘤 将用于自体人源化小鼠模型，并用CTLA4阻断联合On-1治疗。 结肠溶解病毒递送机制增加光的表达。这项拟议的研究具有创新性，因为 肿瘤特异性溶瘤和检查点对CRLM中光表达的多重联合治疗 Blockade将提供一种创造性的方法，这种方法将在患者之间普遍适用。新HORI- 这一创新战略将带来的影响包括对抗CTLA4生物学的更好理解，这可能 不仅提高了应答率，而且极大地增加了它在以前的“冷”肿瘤中的使用适应症， 包括微卫星稳定型胃肠癌。这一贡献将是重大的，因为它将建立- LISH是免疫疗法的协同组合，将对其中一名死者产生直接的翻译影响- 全世界最容易患癌症的人。我们的结果可能会改善患者的生活质量，并提供生存 比目前最好的手术和化疗策略更具优势。

Project Summary/Abstract Colon cancer and colorectal liver metastases (CRLM) are a significant and increasingly lethal disease. Though there is a strong scientific premise to harness the immune system to treat this cancer, there remains a funda- mental gap in understanding of how immunotherapies can be utilized for the majority of these tumors, particu- larly microsatellite stable cancers. The central hypothesis is that the tumor microenvironment can be manipu- lated to enhance cytotoxic lymphocyte infiltration and activation, and that checkpoint blockade can be simulta- neously utilized to incite a clinically relevant immune response. This “one-two punch” hypothesis has been formulated on the basis of preliminary data produced by the applicant where increased T-cell trafficking to tu- mors, when combined with CTLA4 blockade, resulted in complete CRLM regressions. The rationale for the proposed research is that once it is known how to enhance immunostimulatory signals in the microenvironment and simultaneously suppress inhibitory influences, a new strategy for the management of colon cancer is pos- sible. Supported by a very strong scientific premise based on published papers and robust preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine mechanisms to enhance lympho- cyte proliferation and anti-tumor specific immune responses in colon cancer by manipulating immunosuppres- sive signals, 2) Examine mechanisms that supply immunostimulatory influences directly into the tumor; and 3) Combine checkpoint blockade with selective delivery of human LIGHT to treat surgically resected tumors and human CRLM in a pre-clinical autologous system. Under the first aim we expect to increase lymphocyte infiltra- tion, proliferation and activation while simultaneously curbing immunosuppressive signals/cells in the microen- vironment utilizing a validated pre-clinical model established by the applicants. In the second aim, a clinically relevant method to safely increase LIGHT expression within colon cancer tumors using novel tumor-specific viral delivery mechanisms engineered by the applicants will be analyzed. Under the third aim, patient tumors will be utilized in an autologous humanized mouse model and treated with CTLA4 blockade combined with on- colytic viral delivery mechanisms to increase LIGHT expression. The proposed research is innovative, because the multi-combination therapy of LIGHT expression in CRLM with tumor-specific oncolysis and checkpoint blockade will deliver an inventive approach that will be universally applicable from patient to patient. New hori- zons that will stem from this innovative strategy include a better understanding of anti-CTLA4 biology that may not only enhance response rates, but also vastly increase indications for its use in previously “cold” tumors, including microsatellite stable gastrointestinal cancer. This contribution will be significant because it will estab- lish a synergistic combination of immunotherapies that will have direct translational impact on one of the dead- liest cancers worldwide. The implications of our results may improve patient quality of life and provide survival advantages over the best current surgical and chemotherapeutic strategies for this disease.