Neoadjuvant photodynamic immunomodulation for colon cancer

结肠癌新辅助光动力免疫调节

• 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
• 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

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）：在美国，每年有24,702人死于早期结直肠癌手术切除后的复发。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率方面发挥着作用。原发肿瘤中增加的炎症浸润，包括树突状细胞和T-helper-1淋巴细胞，与生存率的提高独立相关。在这个建议中，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。这应该比手术后接种疫苗或其他免疫调节方法有明显的优势。光动力疗法（PDT）包括使用光敏剂，然后在可见光谱中使用固定波长的局部照明，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肿瘤相关抗原在损伤相关分子模式（DAMP）分子的微环境中形成一个储存库，已知这些分子可以激活免疫系统的固有臂和适应性臂，从而启动免疫系统以增强抗肿瘤免疫反应。我们将进行一项初始的I/II期临床研究，以解决中心假设，即在新辅助环境下，通过结肠镜对结肠癌进行腔内PDT治疗是安全可行的，以诱导局部肿瘤细胞死亡和Th1成分增加的炎症/免疫反应。首先，我们将论证结肠镜下新辅助PDT治疗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，这项研究将首次评估PDT在结肠癌新辅助治疗中的免疫调节剂作用。如果我们的假设被证明是正确的，这将提供一种易于实施的治疗策略，没有全身毒性，有可能调节结直肠癌的自然生物学，改善对微转移性肿瘤的控制，降低复发率并提高生存率。