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: 9329390
• 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/9329390
• 关键词: Advisory Committees; Animal Model; Antibodies; Area; Award; Back; Binding; 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; Fc Receptor; Fellowship; Funding; Gastrointestinal Neoplasms; Goals; Grant; Growth and Development function; Head; Hospitals; Human; Illinois; Immune; Immune response; Immune system; Immunologic Markers; Immunologics; Immunology; Immunology procedure; Immunotherapy; Infiltration; Invaded; Journals; Knowledge; Laboratories; 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; Monitor; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Outcome; Paper; Patient Care; Patient-Focused Outcomes; 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; 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; experimental study; improved; insight; interest; invention; knowledge base; laboratory development; lymphoid neoplasm; medical schools; member; mouse model; neoplasm immunotherapy; neoplastic cell; novel; novel therapeutic intervention; overexpression; preclinical study; professor; programs; public health relevance; receptor; response; success; trafficking; training project; translational impact; tumor; tumor immunology; tumor microenvironment; tumor xenograft; tumorigenesis; Advisory Committees; Animal Model; Antibodies; Area; Award; Back; Binding; 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; Fc Receptor; Fellowship; Funding; Gastrointestinal Neoplasms; Goals; Grant; Growth and Development function; Head; Hospitals; Human; Illinois; Immune; Immune response; Immune system; Immunologic Markers; Immunologics; Immunology; Immunology procedure; Immunotherapy; Infiltration; Invaded; Journals; Knowledge; Laboratories; 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; Monitor; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Organ; Outcome; Paper; Patient Care; Patient-Focused Outcomes; 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; 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; experimental study; improved; insight; interest; invention; knowledge base; laboratory development; lymphoid neoplasm; medical schools; member; mouse model; neoplasm immunotherapy; neoplastic cell; novel; novel therapeutic intervention; overexpression; preclinical study; professor; programs; public health relevance; receptor; response; success; trafficking; training project; translational impact; 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（由应用提供）：我是一名外科肿瘤学家，致力于为患有晚期恶性肿瘤的患者携带，并开发新的转移性结肠癌治疗方法。该项目描述了为外科医生科学家职业生涯的5年培训计划，其长期目标是建立一项独立资助的胃肠道肿瘤免疫学研究计划。在我的教育初期，我受到启发研究新的科学方法，以改善患者的结果并追求专门的研究培训项目和心态机会。在布朗大学（Brown University）获得生物学荣誉毕业后，我就读于耶鲁大学医学院，在那里我获得了ADA医学学者Grant，耶鲁大学研究培训补助金和学术外科医生协会（AAS）/诺华奖的有罪研究奖。然后，我在哈佛大学的杨百翰和妇女医院接受了普通外科培训，并选择再花两年的时间在NIH/NCI手术的肿瘤免疫学部门的史蒂文·A·罗森伯格博士的实验室接受肿瘤免疫学和外科肿瘤学培训。在纪念斯隆凯特林癌症中心的临床手术肿瘤学研究金期间，我研究了发育不良的免疫学生物标志物，以及肝转移的免疫浸润，这些肝转移于临床癌症研究和手术肿瘤学的年鉴中发表。我被招募回到芝加哥伊利诺伊大学（UIC）的家乡，加入了一项强大的免疫学计划，并建立了一项研究工作，重点是增强结肠癌肝转移的抗肿瘤免疫新闻，这是我的临床和研究兴趣。该K08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手术兴趣的融合。我们制定了一个完善的培训计划，以确保教育机会，以支持我向独立资金的过渡。我还包括UIC的免疫学和转化科学课程，以扩大我的知识基础。 UIC是我学术成长和发展的理想环境。鉴于渴望在UIC和癌症中心增加转化科学的渴望，我的实验室和职业发展是重中之重，我得到了手术和外科部门的大力支持。我组建了一个由五名专家组成的咨询团队，以监视我的进度，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一个特定的专家领域，以增强我的建议。和发展。 Prabhakar博士是主要的指导者，他对淋巴细胞生物学和免疫疗法的专业知识至关重要。作为微生物和免疫学系负责人，他为我的发展授权了他的指导，实验室，设施和资源。史蒂文·罗森伯格（Steven Rosenberg）博士将担任次要导师，并将从全球肿瘤免疫治疗专家的角度提供批判性见解和批判性。手术系主席，移植免疫学和肝脏手术的权力机构Benedetti博士将确保研究和出版物保留转化枢纽，并且我的时间受到了研究的保护。 Hay博士和Raychaudhuri博士都是人类肝癌的肿瘤发生和动物模型的既定专家，也将担任联合会。所有导师都是终身教授，拥有长期以来的支持研究记录，并结合了数百名学员的成功指导。基于我发表的工作和初步数据，假设是可以使用免疫刺激性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淋巴细胞浸润和功能。我们的实验室优化了有色肝转移和免疫学测定的鼠模型。并开发出表达小鼠结肠癌细胞系的光。我的长期目标是通过针对患者的免疫学系统来增强抗肿瘤反应来改善对晚期结肠癌的控制。该应用的总体目的是找到增加结肠癌肿瘤和转移中抗肿瘤淋巴细胞的浸润和激活的方法。拟议的研究的理由是，一旦知道如何创建免疫刺激性肿瘤微环境，然后再与T-Cells交通到该微环境，这是一种新的转移性结肠癌管理策略，具有持久的抗肿瘤反应的潜力。该提案的第一个目的是通过过表达肿瘤细胞上的免疫刺激性细胞因子光来增加结肠癌肿瘤和肝转移中的淋巴细胞浸润和激活。在第二个具体目标中，我们将测试策略，以利用双特异性抗体（BSAB）对T细胞确定性CD3和表皮生长因子受体（EGFR）进行肿瘤微环境，并过度表达了Colon Cancers的表达。在第三个目标中，我们将进行临床前研究，结合了肿瘤内光的过表达和抗EGFR/CD3 BSAB，以使用人类淋巴细胞和人类结肠癌肿瘤肿瘤在NSG小鼠中增强抗肿瘤免疫调查。免疫学操作可能会产生创造性的“一两次”拳，该冲击普遍适用于患者到患者，以促进抗肿瘤免疫响应，该反应将对全球最致命的癌症之一产生直接翻译影响。