Molecular mechanisms of antibody-mediated immunotherapies

 描述（由申请人提供）：我们在过去二十年的研究集中在阐明抗肿瘤免疫疗法引起其治疗效果的机制。作为我们研究的结果，已经阐明了Fc-FcγR介导的效应子途径对消除肿瘤的重要性，从而优化了第二代抗肿瘤免疫治疗中的这些相互作用，改善了临床活性。虽然这些策略已经导致更有效的抗肿瘤抗体（Abs），显著提高了存活率，但免疫治疗的长期目标是开发将引起肿瘤细胞凋亡的治疗策略。 记忆反应，这将有效地消除复发，从而导致长期生存。目前的建议旨在机械地研究实现这一目标的一般策略，重点是1）使用抗肿瘤单克隆抗体（mAb）诱导肿瘤疫苗接种，2）定义激动性和拮抗性免疫调节mAb增强抗肿瘤疫苗接种的机制，以及3）探索如何操纵肿瘤微环境以增强这些免疫策略。我们的初步结果表明，当适当的Fc-Fc γR相互作用整合到这些抗体中时，抗肿瘤抗体可以引发长期的细胞记忆反应。通过使用Fc优化的免疫调节Ab来操纵细胞效应子应答和肿瘤微环境可以增强这些途径以产生长期记忆应答。

 DESCRIPTION (provided by applicant): Our studies over the past two decades have focused on clarifying the mechanisms by which anti-tumor immunotherapies elicit their therapeutic effects. As a result of our studies, the importance of Fc-FcγR mediated effector pathways for the elimination of tumors has been elucidated, resulting in the optimization of these interactions in second-generation anti-tumor immunotherapeutics with improved clinical activity. While these strategies have resulted in more effective anti-tumor antibodies (Abs) with significantly improved survival, the long-term goal of immunotherapy is to develop therapeutic strategies that will elicit memory responses that will effectively eliminate recurrences and thus result in long-term survival. This current proposal aims to mechanistically investigate general strategies to accomplish this goal by focusing on 1) inducing tumor vaccination using anti-tumor monoclonal Abs (mAbs), 2) define the mechanisms by which agonistic and antagonistic immunomodulatory mAbs enhance anti-tumor vaccination, and 3) explore how the tumor microenvironment may be manipulated in order to augment these immunotherapeutic strategies. Our preliminary results have indicated that anti-tumor Abs can elicit long-term cellular memory responses when appropriate Fc-FcγR interactions are integrated into these Abs. Manipulating both the cellular effector responses and the tumor microenvironment through the use of Fc-optimized immunomodulatory Abs can augment these pathways to result in long-term memory responses.