Enhancing anti-tumor immune responses in colon cancer metastases

增强结肠癌转移的抗肿瘤免疫反应

• 批准号: 8928122
• 负责人: Ajay V. Maker
• 金额: $ 18.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-17 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8928122
• 关键词: Animal Model; Antibodies; Area; Award; Back; Binding; Biological Markers; Biology; Bispecific Antibodies; CD3 Antigens; Cancer Center; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Chairperson; Chicago; Clinical; Clinical Research; Clinical Trials; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Critiques; Cytotoxic T-Lymphocytes; Data; Development; Dysplasia; EGFR Protein Overexpression; Education; Environment; Epidermal Growth Factor Receptor; Fellowship; Funding; Gastrointestinal Neoplasms; Goals; Grant; Growth and Development function; Head; Health; Hospitals; Human; Illinois; Immune; Immune response; Immune system; Immunologics; Immunology; Immunology procedure; Immunotherapy; Infiltration; Invaded; Journals; Knowledge; Laboratories; Light; Liver; Location; Lymphocyte; Lymphocyte Biology; Malignant Neoplasms; Malignant neoplasm of liver; Medical; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metastatic Neoplasm to the Liver; Microbiology; Modeling; Monitor; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Outcome; Paper; Patient Care; Patients; Publications; Publishing; Recruitment Activity; Reporting; Research; Research Support; Research Training; Resected; Resources; Scientist; Solid; Surgeon; Surgical Oncologist; Surgical Oncology; T-Cell Proliferation; T-Lymphocyte; TNM; Tail; Tars; Technology; Testing; Time; Training; Training Programs; Translational Research; Transplantation; United States National Institutes of Health; Universities; Woman; Work; Xenograft procedure; advanced disease; anticancer research; antitumor effect; authority; base; cancer cell; career; career development; colon cancer cell line; cytokine; experience; improved; insight; interest; knowledge base; medical schools; member; neoplastic cell; novel; novel therapeutic intervention; overexpression; preclinical study; professor; programs; receptor; research study; response; success; trafficking; training project; tumor; tumor immunology; tumor microenvironment; tumor xenograft; tumorigenesis

 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.

 描述（由申请人提供）：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。该项目描述了一个为期 5 年的外科医生科学家职业培训计划，其长期目标是建立一个独立资助的胃肠道肿瘤免疫学研究项目。在我接受教育的早期，我受到启发去研究新的科学方法来改善患者的治疗效果，并寻求专门的研究培训项目和指导机会。以优异的成绩从布朗大学生物学专业毕业后，我进入耶鲁大学医学院学习，在那里我获得了 ADA 医学学者补助金、耶鲁大学研究培训补助金以及学术外科医生协会 (AAS)/诺华杰出研究奖。然后，我在哈佛大学布莱根妇女医院接受了普通外科培训，并选择再花两年时间在 NIH/NCI 外科分部肿瘤免疫学部分的 Steven A. Rosenberg 博士的实验室接受肿瘤免疫学和外科肿瘤学培训，在那里我们发表了多份报告，包括《外科肿瘤学年鉴》中的“年度被引用次数最多的文章”和《免疫学杂志》上的机制论文。在纪念斯隆-凯特琳癌症中心进行临床外科肿瘤学研究期间，我研究了不典型增生的免疫生物标志物和肝转移中的免疫浸润，这些结果发表在《临床癌症研究》和《外科肿瘤学年鉴》上。我被招募回到家乡伊利诺伊大学芝加哥分校 (UIC)，加入一个强大的免疫学项目，并开展一项研究工作，重点是增强结肠癌肝转移的抗肿瘤免疫反应，这是我的临床和研究兴趣。这个 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。我们制定了完善的培训计划，以确保教育机会，从而促进我向独立资助的过渡。我还在 UIC 开设了免疫学和转化科学课程，以扩展我在关键领域的知识库。 UIC是我学术成长和发展的理想环境。鉴于伊利诺伊大学芝加哥分校和癌症中心渴望增加转化科学，我的实验室和职业发展是重中之重，我得到了行政部门和外科部门的大力支持。我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。团队的每个成员都提供特定领域的专业知识，以增强我的建议和发展。普拉巴卡博士是主要导师，他在淋巴细胞生物学和免疫治疗方面的专业知识至关重要。作为微生物学和免疫学系的系主任，他为我的发展提供了指导、实验室、设施和资源。 Steven Rosenberg 博士将担任第二导师，将从肿瘤免疫治疗领域的世界专家的角度提供批判性的见解和批评。外科系主任、移植免疫学和肝脏外科权威 Benedetti 博士将确保研究和出版物保留一个转化中心，并保护我的研究时间。 Hay 博士和 Raychaudhuri 博士都是肿瘤发生和人类肝癌动物模型领域的知名专家，他们也将担任共同导师。所有导师都是终身教授，拥有长期支持研究的记录，并成功指导了数百名学员。 根据我发表的工作和初步数据，假设可以使用免疫刺激细胞因子来操纵结肠癌转移的肿瘤微环境，以增强细胞毒性 T 淋巴细胞的浸润和功能。我们的实验室优化了小鼠结直肠肝转移模型和免疫检测；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有针对性地操纵患者的免疫系统来增强抗肿瘤反应，从而改善晚期结肠癌的控制。本申请的总体目标是寻找增加结肠癌肿瘤和转移瘤内抗肿瘤淋巴细胞浸润和活化的方法。这项研究的基本原理是，一旦知道如何创建免疫刺激性肿瘤微环境，然后将 T 细胞运输到该微环境，就有可能开发出一种治疗转移性结肠癌的新策略，并具有持久抗肿瘤反应的潜力。该提案的第一个目标是通过在肿瘤细胞上过度表达免疫刺激细胞因子 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 CD3 和表皮生长因子受体 (EGFR)（在结肠癌中过度表达）的双特异性抗体 (BsAb) 将宿主淋巴细胞运输至肿瘤微环境的策略。第三个目标是，我们将进行临床前研究，将瘤内 LIGHT 过表达和抗 EGFR/CD3 BsAb 相结合，以在 NSG 小鼠中使用人淋巴细胞和人结直肠癌肿瘤移植物增强抗肿瘤免疫反应。免疫操作可能会提供一种创造性的“一二”拳，这种拳在患者之间普遍适用，以激发抗肿瘤免疫反应，这将对全世界最致命的癌症之一产生直接的转化影响。