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

项目总结/摘要 结肠癌和结肠直肠肝转移（CRLM）是一种重要的和日益致命的疾病。虽然 利用免疫系统治疗这种癌症有一个强有力的科学前提，但仍然存在一个基础- 在理解免疫疗法如何用于大多数这些肿瘤方面存在心理差距，特别是 微卫星稳定的癌症。核心假设是肿瘤微环境可以被操纵， 增强细胞毒性淋巴细胞浸润和活化，检查点阻断可以同时进行。 新用于激发临床相关的免疫反应。这种“一拳两拳”的假设一直被 根据申请人提供的初步数据制定，其中增加的T细胞贩运到图- 当与CTLA 4阻断剂组合时，mors导致CRLM完全消退。的理由 拟议的研究是，一旦知道如何增强微环境中的免疫刺激信号， 同时抑制抑制性影响，一种新的结肠癌管理策略是正确的， sible。基于已发表的论文和可靠的初步数据， 这一假设将通过追求三个具体目标来检验：1）确定增强淋巴细胞增殖的机制， 结肠癌细胞增殖和抗肿瘤特异性免疫应答的研究 信号，2）检查直接向肿瘤提供免疫刺激影响的机制;以及3） 将联合收割机检查点阻断与人LIGHT的选择性递送组合以治疗手术切除的肿瘤， 临床前自体系统中的人CRLM。在第一个目标下，我们期望增加淋巴细胞浸润- 同时抑制微环境中的免疫抑制信号/细胞， 使用申请人建立的经验证的临床前模型进行验证。在第二个目标中，临床上 使用新的肿瘤特异性抗体安全地增加结肠癌肿瘤内LIGHT表达的相关方法 将分析由申请人设计的病毒递送机制。在第三个目标下， 将用于自体人源化小鼠模型，并用CTLA 4阻断剂与非人源化治疗相结合进行治疗。 结肠溶病毒递送机制以增加LIGHT表达。这项研究具有创新性，因为 CRLM中LIGHT表达与肿瘤特异性溶瘤和检查点的多重联合治疗 阻断将提供一种将普遍适用于患者的创造性方法。新霍里- 这一创新策略将产生的区域包括更好地理解抗CTLA 4生物学， 不仅提高了反应率，而且大大增加了其在以前“冷”肿瘤中使用的适应症， 包括微卫星稳定的胃肠癌。这一贡献将是重大的，因为它将建立- lish一种免疫疗法的协同组合，将对其中一个死者产生直接的翻译影响- 全世界最严重的癌症我们的研究结果可能会提高患者的生活质量， 与目前治疗该病的最佳手术和化疗策略相比具有优势。

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.