Enhancing the vaccinal effect of antitumor antibodies

描述（由申请人提供）：在过去的二十年中，抗肿瘤抗体疗法对癌症的治疗产生了重大影响，但挑战和机遇仍然存在。对于晚期实体瘤治疗，即使伴随化疗，完全临床缓解也是罕见和短暂的。迫切需要更好地了解常见的治疗和耐药机制，以改善这类新兴的单克隆抗体（mAb）治疗的临床结果。第一个临床成功，利妥昔单抗（抗-CD 20），曲妥珠单抗（抗-HER 2）和西妥昔单抗（抗-EGFR）最初被认为是通过中断其各自的下游信号传导途径。然而，出乎意料的是，我们自己的研究表明，Fc-FcR相互作用是这些药物在小鼠中的功效所必需的，从而定义了效应免疫的重要作用。与我们在小鼠中的观察结果一致，一些临床研究已经将携带较高IgG亲和力FcR等位基因的癌症患者的有利临床结果相关联。FcR介导的免疫机制已被统称为“抗体依赖性细胞毒性”（ADCC），这一概念源于对携带细胞毒性FcR的先天效应物（巨噬细胞、嗜中性粒细胞和NK细胞）的体外观察，其在数小时内快速杀死IgG包被的肿瘤细胞。然而在体内，除了利妥昔单抗介导的血液中正常和恶性B细胞的清除（例如，CLL），几乎没有证据表明实体瘤治疗会产生“ADCC样”急性炎症反应。相反，肿瘤反应的较慢动力学与诱导的适应性免疫反应更一致，作为对联合化疗和抗肿瘤抗体的“疫苗”反应而引发。在该模型中，凋亡/坏死物质的抗体调理作用提供了调节抗原呈递细胞摄取肿瘤抗原的免疫学结果的治疗窗口。我们最近的研究证明了这种疫苗途径在接受化疗+曲妥珠单抗治疗的乳腺癌患者中的临床相关性。接受该方案治疗的患者产生了抗肿瘤HER-2特异性免疫，我们发现这种免疫在具有良好临床结局的患者中富集，表明“被动”mAb治疗诱导了可能有助于疗效的“主动”肿瘤免疫。在本提案中，我们将进一步从机制上定义疫苗途径的重要性（目标1），并努力使用两种创新方法来增强这些效果。我们将首先使用抗肿瘤抗体，选择性地激活树突状细胞上的人Fc受体（Aim 2），其次，我们将使用药理学策略阻断限制T细胞活化的抑制性途径（Aim 3）。我们的目的旨在检验以下假设：去除负调控途径可以促进这种抗体增强的抗原递送的爆发，从而产生有效的抗肿瘤细胞T细胞，并将次优的抗肿瘤治疗反应转化为有意义的临床获益。

DESCRIPTION (provided by applicant): Antitumor antibody therapeutics have significantly impacted the treatment of cancer over the past two decades, yet challenges and opportunities remain. For advanced stage solid tumor treatment, complete clinical remissions are infrequent and transient, even with concomitant chemotherapy. A better understanding of the common therapeutic and resistance mechanisms is urgently needed to improve clinical outcomes of this emerging class of monoclonal antibody (mAb) therapeutics. The first clinical successes, Rituximab (anti-CD20), Trastuzumab (anti- HER2) and Cetuximab (anti-EGFR) were initially thought to work exclusively through interruption of their respective downstream signaling pathways. Unexpectedly, however, our own studies demonstrated that Fc-FcR interactions were required for efficacy of these drugs in the mouse, defining an essential role for effector immunity. Consistent with our observations in mice, several clinical studies have since correlated favorable clinical outcomes in cancer patients harboring higher IgG affinity FcR alleles. The FcR-mediated immunological mechanisms have been collectively described as 'antibody- dependent cellular cytotoxicity' (ADCC), a concept that stems from in vitro observations of cytotoxic FcR-bearing innate effectors (macrophages, neutrophils and NK cells) that rapidly kill IgG-coated tumor cells, within hours. Yet in vivo, with the exception of Rituximab-mediated clearance of normal and malignant B cells in the blood (e.g., CLL), there is little evidence for an 'ADCC-like' acute inflammatory response for solid tumor treatment. Instead, the slower kinetics of tumor responses are more consistent with an induced adaptive immune response, elicited as a "vaccinal" response to combination chemotherapy and antitumor antibodies. In this model, antibody opsonization of apoptotic/necrotic material provides a therapeutic window to modulate the immunological outcome of tumor antigen uptake by antigen presenting cells. Our recent studies demonstrated clinical relevance of this vaccinal pathway in breast cancer patients treated with chemotherapy + trastuzumab. Patients treated with this regimen developed antitumor HER-2 specific immunity, which we found were enriched in patients with favorable clinical outcomes, indicating that "passive" mAb therapy induces "active" tumor immunity that may contribute to efficacy. In this proposal, we will further define the importance of the vaccinal pathway mechanistically (Aim 1) and pursue efforts to enhance these effects using two innovative approaches. We will first use antitumor antibodies engineered to selectively engage activating human Fc receptors on dendritic cells (Aim 2), and secondly, we will use pharmacologic strategies to block inhibitory pathways that limit T cell activation (Aim 3). Our Aims are designed to test the hypothesis that removal of negative regulatory pathways could promote this burst of antibody-enhanced antigen delivery, leading to effective anti-tumor cell T cell generation and conversion of a suboptimal antitumor treatment response into meaningful clinical benefit.