Molecular mechanisms of antibody-mediated immunotherapies

 描述(申请人提供)：在过去的二十年里，我们的研究集中于阐明抗肿瘤免疫疗法产生治疗效果的机制。作为我们研究的结果，Fc-FcγR介导的效应通路在消除肿瘤中的重要性已经被阐明，从而使这些相互作用在第二代抗肿瘤免疫疗法中得到优化，并提高了临床活性。虽然这些策略已经导致了更有效的抗肿瘤抗体(Abs)，并显著提高了存活率，但免疫疗法的长期目标是开发出能够诱导 记忆反应将有效地消除复发，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，主要集中在1)使用抗肿瘤单抗诱导肿瘤疫苗接种，2)确定激动型和拮抗型免疫调节单抗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治疗策略。我们的初步结果表明，当适当的Fc-FcγR相互作用整合到抗肿瘤抗体中时，这些抗体可以诱导长期的细胞记忆反应。通过使用FC优化的免疫调节抗体来操纵细胞效应反应和肿瘤微环境，可以增强这些途径，从而产生长期记忆反应。

 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.