Immunomodulation in melanoma: Toll like receptors and therapeutic vaccines

描述（由申请人提供）：项目摘要：Craft博士于2005年7月在洛杉矶生物医学研究所的支持下，在Harbor-UCLA医学中心建立了他的独立研究项目，专注于肿瘤免疫治疗。环境是非常支持新的研究人员在相关生物医学领域的世界领导者之间的转化研究中做出创造性和创业性的努力。本提案的短期目标是确定Toll样受体（TLR）增强抗黑色素瘤疫苗的机制，并使用小鼠黑色素瘤模型优化疫苗策略。长期目标是为正在进行的转化研究提供机制基础，旨在为患有黑色素瘤的人类开发现实的靶向免疫疗法。这些长期研究将与一个多学科研究小组合作，并将成为未来R 01和其他资助机制的主题。TLR是免疫系统对病原体产生宿主防御能力的关键部分。初步数据表明，TLR 7激动剂咪喹莫特是用表达黑色素瘤抗原的重组单核细胞增生李斯特菌（rLM）免疫的有效佐剂，并导致对黑色素瘤的深刻保护。我们假设TLR 7/8的刺激导致树突状细胞（DC）的活化，在疫苗诱导的CD 8 + T细胞的情况下，树突状细胞（DC）导致表位扩散和肿瘤清除。目的1使用小鼠黑色素瘤模型来确定参与基于rLM的抗黑色素瘤疫苗的TLR 7/8增强的分子机制。目的2将研究TLR 7/8活化对基于DC的疫苗的影响，并优化使用DC和rLM的黑色素瘤免疫治疗的组合方法。相关性：黑色素瘤是一种常见的癌症，也是导致生产年损失的主要原因。许多针对黑色素瘤的积极试验用免疫疗法靶向肿瘤抗原。该建议旨在了解宿主免疫和自身耐受之间的关系，因为它涉及肿瘤免疫治疗。这些研究将提高我们对抗肿瘤免疫机制的理解，并将增强未来黑色素瘤和其他免疫原性较低的癌症的免疫疗法的设计。这笔赠款将为申请人在其职业生涯的最初几年提供至关重要的资金，其结果将成为开发现实的抗黑色素瘤疫苗和疫苗佐剂的垫脚石。

DESCRIPTION (provided by applicant): Project Summary: Dr. Craft established his independent research program in July 2005, focusing on tumor immunotherapy at Harbor-UCLA Medical Center with support from the LA Biomedical Research Institute. The environment is extremely supportive of new investigators making creative and entrepreneurial efforts in translational research amongst world leaders in related biomedical fields. The short term goals of this proposal are to define the mechanism of Toll-like receptor (TLR) enhancement of anti-melanoma vaccines and to optimize the vaccine strategies using a mouse model of melanoma. The long term goals are to provide a mechanistic foundation for the ongoing translational studies aimed at development of realistic targeted immunotherapies for humans with melanoma. These long term studies will be in collaboration with a multidisciplinary group of investigators and will be the subject of future R01 and other grant mechanisms. TLRs are a critical part of the immune system's ability to generate host defense to pathogens. Preliminary data suggests that the TLR7 agonist, imiquimod, is an effective adjuvant to immunization with recombinant Listeria monocytogenes (rLM) expressing melanoma antigens and leads to profound protection from melanoma. We hypothesize that stimulation of TLR7/8 leads to activation of dendritic cells (DCs) that in the context of vaccine induced CD8+ T cells leads to epitope spreading and tumor clearance. Aim 1 uses a mouse melanoma model to determine the molecular mechanism involved in TLR7/8 enhancement of an rLM-based anti-melanoma vaccine. Aim 2 will study the effects of TLR7/8 activation on DC based vaccines and optimize a combinatorial approach to melanoma immunotherapy using both DCs and rLM. Relevance: melanoma is a common cancer and a leading cause of loss of productive years. Many active trials for melanoma target tumor antigens with immunotherapy. This proposal is aimed at understanding the relationship between host immunity and self tolerance as it relates to tumor immunotherapy. These studies will improve our understanding of the mechanisms involved in anti-tumor immunity and will enhance the design of future immunotherapies for melanoma and other, less immunogenic cancers. This grant will provide the applicant with crucial funding during the initial independent years of his career and the results will be a stepping stone to development of realistic anti-melanoma vaccines and vaccine adjuvants.