Enhancing anti-tumor immune responses in colon cancer metastases

 描述（由申请人提供）：我是一名外科肿瘤学家，致力于治疗晚期恶性肿瘤患者，并开发转移性结肠癌的新治疗方法。该项目描述了一个为期5年的培训计划，作为一个外科医生，科学家的职业生涯，建立一个独立资助的研究计划，在胃肠道肿瘤免疫学的长期目标。在我的教育早期，我受到启发，研究新的科学方法，以改善病人的结果，并追求专门的研究培训项目和导师的机会。从布朗大学以优异的成绩毕业后，我就读于耶鲁大学医学院，在那里我被授予ADA医学学者奖，耶鲁大学研究培训赠款，以及学术外科医生协会（AAS）/诺华奖。然后，我在哈佛大学布里格姆妇女医院接受普通外科培训，并选择在Steven A. Rosenberg在NIH/NCI外科分支的肿瘤免疫学部分发表了多篇报告，包括《外科肿瘤学年鉴》上的“年度引用最多的文章”和《免疫学杂志》上的一篇机制论文。在纪念斯隆-凯特琳癌症中心的临床外科肿瘤学研究期间，我研究了异型增生的免疫学生物标志物，以及肝转移的免疫浸润，这些研究发表在临床癌症研究和外科肿瘤学年鉴上。我被招募回到我的家乡在伊利诺伊大学芝加哥（UIC）加入一个强大的免疫学计划，并建立一个研究工作，重点是提高抗肿瘤免疫反应在结肠癌肝转移，我的临床和研究兴趣。这个K 08提案是我职业发展的关键一步，因为该项目代表了我对肿瘤免疫学的热情与我的临床和外科兴趣的融合。我们已经制定了一个完善的培训计划，以确保教育机会，这将有助于我向独立资助过渡。我还在UIC学习了免疫学和转化科学课程，以扩大我在关键领域的知识基础。UIC是我学术成长和发展的理想环境。鉴于在UIC和癌症中心增加转化科学的愿望，我的实验室和职业发展是重中之重，我从行政部门和外科得到了巨大的支持。我已经组建了一个由五位专家组成的顾问团队来监督我的进展，支持我的研究，并促进我的职业发展。团队中的每个成员都提供了一个特定的专业领域，以增强我的建议和发展。Prabhakar博士是主要的导师，他在淋巴细胞生物学和免疫治疗方面的专业知识将是至关重要的。作为微生物学和免疫学系主任，他为我的发展提供了指导、实验室、设施和资源。史蒂文·罗森伯格博士将担任二级导师，并将从世界肿瘤免疫治疗专家的角度提供关键的见解和批评。Benedetti博士是外科系主任，也是移植免疫学和肝脏手术的权威，他将确保研究和出版物保留一个翻译中心，并保护我的时间用于研究。Hay博士和Raychaudhuri博士都是肿瘤发生和人类肝癌动物模型方面的专家，他们也将担任共同导师。所有导师都是终身教授，拥有长期的支持研究记录，并成功指导了数百名学员。 基于我已发表的工作和初步数据，假设结肠癌转移的肿瘤微环境可以使用免疫刺激细胞因子来操纵，以增强细胞毒性T淋巴细胞的浸润和功能。我们的实验室已经优化了结肠直肠肝转移的小鼠模型和免疫学测定;并开发了表达LIGHT的小鼠结肠癌细胞系。我的长期目标是通过靶向操纵患者的免疫系统来增强抗肿瘤反应，从而改善对晚期结肠癌的控制。本申请的总体目标是找到增加结肠癌肿瘤和转移瘤内抗肿瘤淋巴细胞的浸润和活化的方法。这项研究的基本原理是，一旦知道如何创造一个免疫刺激性肿瘤微环境，然后将T细胞运送到该微环境中，一种具有持久抗肿瘤反应潜力的转移性结肠癌管理新策略就成为可能。该提议的第一个目的是通过在肿瘤细胞上过表达免疫刺激性细胞因子LIGHT来增加结肠癌肿瘤和肝转移瘤内的淋巴细胞浸润和活化。在第二个具体目标中，我们将测试利用针对T细胞决定簇CD 3和表皮生长因子受体（EGFR）的双特异性抗体（BsAb）将宿主淋巴细胞运输到肿瘤微环境的策略，EGFR在结肠癌中过表达。在第三个目标中，我们将在NSG小鼠中使用人淋巴细胞和人结直肠癌肿瘤移植物进行结合肿瘤内LIGHT过表达和抗EGFR/CD 3 BsAb的临床前研究，以增强抗肿瘤免疫应答。可能的是，免疫学操作将递送本发明的“一-二”冲击，其普遍适用于患者之间以激发抗肿瘤免疫应答，其将对世界上最致命的癌症之一具有直接的转化影响。

 DESCRIPTION (provided by applicant): I am a surgical oncologist dedicated to caring for patients with advanced malignancies and to developing novel therapeutic approaches for metastatic colon cancer. This project describes a 5-year training program for a career as a surgeon-scientist with the long-term goal of establishing an independently funded research program in gastrointestinal tumor immunology. Early in my education, I was inspired to study new scientific approaches to improve patient outcomes and pursued dedicated research training projects and mentorship opportunities. After graduating with honors in biology from Brown University, I attended Yale School of Medicine where I was awarded the ADA Medical Scholar Grant, Yale research training grants, and the Association for Academic Surgeons (AAS)/Novartis Award for meritorious research. I then trained in general surgery at Harvard University's Brigham and Women's Hospital and chose to devote two additional years to receive tumor immunology and surgical oncology training in the laboratory of Dr. Steven A. Rosenberg in the Tumor Immunology section of the NIH/NCI Surgery Branch where we published multiple reports including "the most cited article of the year" in the Annals of Surgical Oncology and a mechanism paper in the Journal of Immunology. During my clinical surgical oncology fellowship at Memorial Sloan-Kettering Cancer Center, I studied immunologic biomarkers of dysplasia, and immune infiltrates in liver metastases, which were published in Clinical Cancer Research and the Annals of Surgical Oncology. I was recruited back to my hometown at the University of Illinois at Chicago (UIC) to join a strong immunology program and to build a research effort focused on enhancing anti-tumor immune responses in colon cancer liver metastases, my clinical and research interests. This K08 proposal is a critical step in my career development as the project represents a fusion of my passion for tumor immunology with my clinical and surgical interests. We have created a well-developed training plan to insure educational opportunities that will facilitate my transition toward independent funding. I have also included immunology and translational science coursework at UIC to expand my knowledge base in critical are- as. UIC is an ideal environment for my academic growth and development. Given a desire for increased translational science at UIC and the Cancer Center, my laboratory and career development are top priorities and I receive a tremendous level of support from the administration and Department of Surgery. I have assembled an advisory team of five experts to monitor my progress, support my research, and promote my career development. Each member of the team offers a particular area of expertise that enhances my proposal and development. Dr. Prabhakar is the primary mentor, and his expert knowledge of lymphocyte biology and immunotherapy will be paramount. As head of the Department of Microbiology and Immunology, he has committed his mentorship, lab, facilities, and resources for my development. Dr. Steven Rosenberg will serve as secondary mentor and will provide critical insight and critique from the perspective of a world's expert in tumor immuno- therapy. Dr. Benedetti, Chairman of the Department of Surgery and an authority on transplant immunology and liver surgery, will insure that the research and publications preserve a translational hub and that my time is protected for research. Dr. Hay and Dr. Raychaudhuri, both established experts in tumorigenesis and animal models of human liver cancers, will also serve as co-mentors. All mentors are tenured professors with a long record of supported research and combined successful mentorship of hundreds of trainees. Based on my published work and preliminary data, the hypothesis is that the tumor microenvironment of colon cancer metastases can be manipulated using immunostimulatory cytokines to enhance cytotoxic T lymphocyte infiltration and function. Our lab has optimized a murine model of colorectal liver metastases and immunologic assays; and developed a LIGHT expressing mouse colon cancer cell line. My long-term goal is to improve the control of advanced colon cancer by enhancing anti-tumor responses through targeted manipulation of the patient's immune system. The overall objective of this application is to find ways of increasing the infiltration and activation of anti-tumor lymphocytes within colon cancer tumors and metastases. The rationale for the proposed research is that, once it is known how to create an immunostimulatory tumor microenvironment and then also to traffic T-cells to that microenvironment, a new strategy for the management of metastatic colon cancer with the potential for durable anti-tumor responses is possible. The first aim of this proposal is to increase lymphocyte infiltration and activation within colon cancer tumors and liver metastases by overexpressing the immunostimulatory cytokine LIGHT on tumor cells. In the second specific aim, we will test strategies to traffic host lymphocytes to the tumor microenvironment utilizing a bispecific antibody (BsAb) to the T-cell determinant CD3, and the epidermal growth factor receptor (EGFR), which is overexpressed on colon cancers. In the third aim, we will perform pre-clinical studies combining intratumoral LIGHT overexpression and an anti- EGFR/CD3 BsAb to enhance anti-tumor immune responses using human lymphocytes and human colorectal cancer tumorgrafts in NSG mice. It is possible that the immunologic manipulations will deliver an inventive "one-two" punch that is universally applicable from patient to patient to incite an anti-tumor immune response that will have direct translational impact on one of the deadliest cancers worldwide.