Molecular mechanisms of antibody-mediated immunotherapies

摘要 在过去的二十年里，我们的研究集中在阐明抗肿瘤的机制， 免疫疗法引起它们的治疗效果。作为我们研究的结果，Fc-FcγR介导的重要性 已经阐明了消除肿瘤的效应途径，导致这些效应途径的优化。 在第二代抗肿瘤免疫治疗中的相互作用具有改善的临床活性。之一 作为我们以前资助的NCI研究的一部分开发的疗法现在正在三项临床试验中进行测试 早期证据表明有希望的活动。虽然通过Fc改善基于抗体的治疗的策略 工程化已经产生了更有效的抗肿瘤抗体（Ab），具有显著改善的存活率， 免疫疗法的长期目标是开发治疗策略， 有效地消除复发，从而提高总体生存率。目前的建议旨在 机械地研究一般策略，以实现这一目标，重点是1）诱导肿瘤 使用抗肿瘤单克隆抗体（mAb）的疫苗接种，2）定义激动性和 拮抗性免疫调节单克隆抗体增强抗肿瘤疫苗接种，以及3）探索肿瘤如何 可以操纵微环境以改善这些免疫策略。我们的初步结果 已经表明，当适当的Fc-Fc γR时，抗肿瘤抗体可以引起长期的细胞记忆反应， 相互作用被整合到这些Ab中。操纵细胞效应器反应和肿瘤 通过使用Fc优化的免疫调节Ab，微环境可以进一步增强这些免疫调节活性。 并导致长期记忆反应。

ABSTRACT 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. One of the therapies developed as part of our previously funded NCI studies is now being tested across three clinical trials with early evidence of promising activity. While strategies improving antibody-based therapeutics through Fc engineering 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 and effectively eliminate recurrences, resulting in improvements in overall 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 to improve 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 further augment these pathways and result in long-term memory responses.