Neoadjuvant photodynamic immunomodulation for colon cancer

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，这些癌症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作用。原发性肿瘤中炎性浸润的增加，包括树突状细胞和辅助性T淋巴细胞1的存在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）诱导免疫反应，而肿瘤在原位，最大限度地提高抗肿瘤免疫反应的强度和广度。这应该比手术后疫苗或其他免疫调节方法具有明显的优势。光动力疗法（PDT）涉及施用光敏剂，然后用可见光谱中的固定波长进行局部照射，产生局部细胞毒性效应和局部炎症/免疫应答。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的储库，已知所述DAMP分子激活免疫系统的先天性和适应性臂两者，导致免疫系统引发增加的抗肿瘤免疫应答。我们将进行一项初步的I/II期临床研究，以解决中心假设，即在新辅助治疗环境中，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Th 1组分增加的炎症/免疫应答。首先，我们将证明结肠镜下新辅助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应答的影响。据我们所知，这项研究将是第一次评估PDT作为免疫调节剂在结肠癌新辅助治疗中的作用。如果我们的假设被证明是正确的，这将提供一种易于管理的治疗策略，没有全身毒性，有可能调节结直肠癌的自然生物学，改善微转移肿瘤的控制，降低复发率和提高生存率。 公共卫生相关性：需要新的方法来减少结肠癌手术切除患者的复发率，结肠癌是美国女性和男性癌症死亡的第三大常见原因。我们将测试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应答的假设。这些研究可能为开发提高结肠癌生存率的新策略提供基础。

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.