Enhancing anti-tumor immune responses in colon cancer metastases

 描述(申请人提供)：我是一名外科肿瘤学家，致力于护理晚期恶性肿瘤患者，并开发转移性结肠癌的新治疗方法。这个项目描述了一个为期5年的外科医生-科学家职业生涯培训计划，长期目标是建立一个独立资助的胃肠道肿瘤免疫学研究计划。在我接受教育的早期，我受到启发，研究新的科学方法来改善患者的预后，并寻求专门的研究培训项目和指导机会。我以优异的成绩从布朗大学生物学专业毕业后，就读于耶鲁医学院，在那里我获得了ADA医学学者助学金、耶鲁大学研究培训助学金，以及学术外科医生协会(AAS)/诺华杰出研究奖。然后我在哈佛大学的布里格姆和妇女医院接受了普通外科的培训，并选择再花两年的时间在NIH/NCI外科分部肿瘤免疫科的Steven A.Rosenberg博士的实验室接受肿瘤免疫学和外科肿瘤学培训，我们在那里发表了多篇报告，包括在《外科肿瘤学年鉴》上发表的“年度被引用最多的文章”和在《免疫学杂志》上发表的一篇机制论文。在纪念斯隆-凯特琳癌症中心担任临床外科肿瘤学研究员期间，我研究了异型增生的免疫生物标记物和肝转移的免疫浸润物，这些研究发表在《临床癌症研究》和《外科肿瘤学年鉴》上。我被招募回家乡的伊利诺伊大学芝加哥分校(UIC)，加入一个强大的免疫学项目，并建立一个专注于增强结肠癌肝转移抗肿瘤免疫反应的研究工作，这是我的临床和研究兴趣。这份K08提案是我职业发展中的关键一步，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，这将促进我向独立资助的过渡。我还在UIC开设了免疫学和翻译科学课程，以扩大我在关键领域的知识基础。UIC是我学业成长和发展的理想环境。鉴于UIC和癌症中心渴望增加翻译科学，我的实验室和职业发展是重中之重，我从行政部门和外科部门得到了极大的支持。我组建了一个由五名专家组成的顾问团队，以监督我的进展，支持我的研究，并促进我的职业发展。团队中的每一位成员都提供了一个特定的专业领域，以加强我的提案和开发。普拉巴卡尔博士是主要导师，他在淋巴细胞生物学和免疫疗法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的主任，他致力于为我的发展提供指导、实验室、设施和资源。史蒂文·罗森博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批判性的见解和批评。贝内代蒂博士是外科主任，也是移植免疫学和肝脏外科方面的权威，他将确保研究和出版物保留翻译中心，并保护我的研究时间。海伊博士和雷乔杜里博士都是肿瘤发生和人类肝癌动物模型方面的资深专家，他们也将担任共同导师。所有导师都是终身教授，有着长期的研究支持记录，并成功地指导了数百名学员。根据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通过免疫刺激细胞因子来增强细胞毒性T淋巴细胞的渗透和功能。我们的实验室优化了结直肠癌肝转移的小鼠模型和免疫学检测；并开发了表达LIGH的小鼠结肠癌细胞系。我的长期目标是通过对患者免疫系统的有针对性的操作来增强抗肿瘤反应，从而改善晚期结肠癌的控制。这一应用的总体目标是寻找增加抗肿瘤淋巴细胞在结肠癌肿瘤和转移中的渗透和激活的方法。这项拟议研究的基本原理是，一旦知道如何创造免疫刺激的肿瘤微环境，然后将T细胞输送到该微环境，就有可能采用一种新的策略来管理转移性结肠癌，并有可能产生持久的抗肿瘤反应。这项建议的第一个目的是通过在肿瘤细胞上过度表达免疫刺激细胞因子光来增加结肠癌和肝转移瘤中淋巴细胞的渗透和激活。在第二个特定目标中，我们将测试利用针对T细胞决定簇CD3的双特异性抗体(BsAb)和在结肠癌上过度表达的表皮生长因子受体(EGFR)，将宿主淋巴细胞运输到肿瘤微环境的策略。在第三个目标中，我们将开展结合瘤内光过表达和抗EGFR/CD3 BsAb的临床前研究，以增强NSG小鼠体内的人淋巴细胞和人结直肠癌移植瘤的抗肿瘤免疫反应。这种免疫操作可能会产生一种创造性的、普遍适用于不同患者的“1-2”重击，以激发抗肿瘤免疫反应，从而对世界上最致命的癌症之一产生直接的翻译影响。

 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.