Neoadjuvant photodynamic immunomodulation for colon cancer

结肠癌新辅助光动力免疫调节

基本信息

批准号：
8005456
负责人：
RANDALL F HOLCOMBE
金额：
$ 29.82万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8005456
关键词：
Acids Address Adjuvant Chemotherapy Biology CD8-Positive T-Lymphocytes Cancer Etiology Cancer Patient Cell Death Cells Cessation of life Characteristics Cholangiocarcinoma Clinical Research Colon Carcinoma Colonoscopes Colonoscopy Colorectal Colorectal Cancer Dendritic Cells Development Diagnosis Disease Endoscopes Evaluation Excision Gastrointestinal Neoplasms Gender Grant Hour Image Immune response Immune system Immunohistochemistry Immunomodulators Immunosuppressive Agents Immunotherapy In Situ Incidence Inflammatory Inflammatory Infiltrate Knowledge Lasers Lesion Light Lighting Lymphocyte Malignant Neoplasms Measures Messenger RNA Methods Molecular Molecular Profiling Monitor Myelogenous Neoadjuvant Therapy Operative Surgical Procedures Patients Pattern Phase Photochemotherapy Photosensitizing Agents Plague Play Polyps Population Primary Neoplasm Prodrugs Proteins Quality of life Recurrence Relapse Reporting Role Safety Screening procedure Site Staging Surgical complication T-Lymphocyte Testing Therapeutic Tissues Toxic effect Tumor Antigens Tumor Immunity United States Vaccines Vascular Endothelial Growth Factors Woman arm base cell injury cytokine cytotoxic image guided intervention immunoregulation improved lymph nodes macrophage men mortality neoplastic neoplastic cell novel strategies palliation peripheral blood protoporphyrin IX public health relevance response tumor

项目摘要

DESCRIPTION (provided by applicant): 24,702 people die in the United States each year because of recurrence following surgical resection of early stage colorectal cancer that might be eliminated with new approaches. There is increasing evidence that the immune system plays a role in controlling micrometastic colorectal cancer and in determining survival. The presence of an increased inflammatory infiltrate in primary tumors, including dendritic cells and T-helper-1 lymphocytes has been independently associated with improved survival. In this proposal we will utilize neoadjuvant photodynamic therapy (PDT) to induce the immune response while the tumor is in situ, maximizing the strength and breadth of the anti-tumor immune response. This should have marked advantages over post-surgical vaccine or other immunomodulatory approaches. Photodynamic therapy (PDT) involves the administration of photosensitizer followed by local illumination with a fixed wavelength in the visible spectrum, generating a localized cytotoxic effect and a local inflammatory/immune response. The localized tissue damage and cell death leads to the formation of a depot of tumor-associated antigens in a microenvironment of damage-associated molecular pattern (DAMP) molecules that are known to activate both the innate and adaptive arms of the immune system leading to priming of the immune system for increased anti-tumor immune responses. We will conduct an initial, phase I/II clinical study to address the central hypothesis that it is safe and feasible to administer intraluminal PDT to colon cancers, via colonoscopy, in the neoadjuvant setting to induce localized tumor cell death and an inflammatory/immune response with an increased Th1 component. First, we will demonstrate the feasibility and safety of colonoscopic, neoadjuvant PDT for colon cancer patients. Next, we will characterize the inflammatory and immune response induced by PDT at the tumor site. Finally, we will evaluate the impact of neoadjuvant PDT on the regional and systemic anti-tumor immune response. To our knowledge this study will be the first evaluation of PDT as an immunomodulator in the neoadjuvant setting for colon cancer. If our hypothesis is demonstrated to be correct, this will provide an easily administered therapeutic maneuver that lacks systemic toxicity, with the potential to modulate the natural biology of colorectal cancers, improve control of micrometastatic tumor, decrease relapse rates and improve survival. PUBLIC HEALTH RELEVANCE: New approaches are needed to reduce the incidence of relapse for patients undergoing surgical resection of colon cancer, the third most common cause of cancer death for women and men in the United States. We will test the hypothesis that neoadjuvant photodynamic therapy will induce an inflammatory and immune response directed against tumor antigens within the tumor microenvironment. These studies may provide the basis for the development of new strategies to improve colon cancer survival.

描述（由申请人提供）：美国每年有 24,702 人因手术切除早期结直肠癌后复发而死亡，而早期结直肠癌可能会通过新方法消除。越来越多的证据表明，免疫系统在控制微转移性结直肠癌和决定生存方面发挥着重要作用。原发性肿瘤（包括树突状细胞和 T-helper-1 淋巴细胞）中炎症浸润的增加与生存率的提高独立相关。在该提案中，我们将利用新辅助光动力疗法（PDT）在肿瘤原位诱导免疫反应，最大限度地提高抗肿瘤免疫反应的强度和广度。与术后疫苗或其他免疫调节方法相比，这应该具有明显的优势。光动力疗法（PDT）涉及施用光敏剂，然后用可见光谱中固定波长进行局部照明，产生局部细胞毒性作用和局部炎症/免疫反应。局部组织损伤和细胞死亡导致在损伤相关分子模式（DAMP）分子的微环境中形成肿瘤相关抗原库，这些分子已知可以激活免疫系统的先天性和适应性臂，从而导致启动免疫系统增强抗肿瘤免疫反应。我们将进行一项初步的 I/II 期临床研究，以解决以下中心假设：在新辅助治疗环境中，通过结肠镜检查对结肠癌进行腔内 PDT 诱导局部肿瘤细胞死亡和炎症/免疫反应是安全可行的Th1 成分增加。首先，我们将证明结肠镜新辅助 PDT 对结肠癌患者的可行性和安全性。接下来，我们将描述 PDT 在肿瘤部位诱导的炎症和免疫反应。最后，我们将评估新辅助PDT对局部和全身抗肿瘤免疫反应的影响。据我们所知，这项研究将是首次评估 PDT 作为结肠癌新辅助治疗中的免疫调节剂。如果我们的假设被证明是正确的，这将提供一种易于实施且缺乏全身毒性的治疗策略，并有可能调节结直肠癌的自然生物学，改善对微转移肿瘤的控制，降低复发率并提高生存率。公共卫生相关性：需要新的方法来降低接受结肠癌手术切除的患者的复发率，结肠癌是美国女性和男性癌症死亡的第三大常见原因。我们将检验新辅助光动力疗法将诱导针对肿瘤微环境内的肿瘤抗原的炎症和免疫反应的假设。这些研究可能为开发改善结肠癌生存的新策略提供基础。