Checkpoint Receptor Targeting to Enhance Cetuximab Efficacy Against HNSCC

项目概要项目3 尽管在几乎所有的头颈部鳞状上皮细胞中表皮生长因子受体（EGFR）过度表达， EGFR特异性单克隆抗体（mAb）西妥昔单抗仅在HNSCC中有效。 少数患者。西妥昔单抗的温和作用激发了人们对确定其抗肿瘤作用的兴趣。 机制和限制临床反应的因素，以提高其疗效， 免疫力接近。越来越多的证据和我们的初步结果表明， 抗原（TA）特异性mAb，如西妥昔单抗，可以有效地触发TA特异性细胞毒性T淋巴细胞（CTL） 应答然而，这些效应CTL并不完全有效，提高了抑制性CTL的可能性。 这些机制限制了西妥昔单抗在大多数患者中的疗效。阻断这些抑制性 这些机制可以恢复抗肿瘤活性并增强西妥昔单抗的功效。然而，抑制 限制西妥昔单抗疗效的主要机制仍不清楚。高频 外周血T淋巴细胞（PBL）和肿瘤浸润T淋巴细胞（TIL）在多种实体瘤中的表达， 包括HNSCC，表达升高水平的抑制性受体（所谓的“检查点”），例如细胞毒性T细胞（CTL）， 淋巴细胞抗原（CTLA-4）和程序性死亡-1（PD-1），使它们对抗原性无反应 刺激（耗竭）。此外，CTLA-4+调节性T细胞（TCL 4），一种有效的抑制性辅助细胞， 产生TGF-β的CD 4 + T细胞群体通常以增加的频率存在，并且具有增强的 抑制肿瘤的能力。总的来说，CTL和T细胞上的抑制性受体是细胞增殖的主要障碍。 有效的抗肿瘤T细胞反应，这已被证明是惊人的临床反应，以抗- CTLA-4和抗PD-1抗体。我们以前的研究和初步数据支持一个工作模型， 西妥昔单抗在无应答患者中触发TA特异性CD 8 + T细胞的产生 人群同时发生增加的抑制机制（包括TGF-β），减少临床 对西妥昔单抗治疗的反应。该项目将利用来自两个国家的生物标本， 新的UPCI临床试验，最近完成（UPCI 08-013，测试免疫生物标志物， 西妥昔单抗单药治疗患者）或正在进行中（UPCI 12-084，西妥昔单抗与抗CTLA-4联合治疗 mAb伊匹单抗以抑制Treg）。我们将确定是否抑制机制负责限制 在西妥昔单抗治疗的HNSCC患者中诱导的抗肿瘤活性，并直接评估CTLA 4 + 在这个新的，正在进行的临床试验中。

Project Summary Project 3 Despite overexpression of the epidermal growth factor receptor (EGFR) on nearly all head and neck squamous cell carcinomas (HNSCC), the EGFR-specific monoclonal antibody (mAb) cetuximab is effective only in a minority of patients. The modest effects of cetuximab have stimulated interest in determining its anti-tumor mechanisms and the factors that limit clinical responses, in order to improve its efficacy by combining immunotherapeutic approaches. A growing body of evidence, and our preliminary results, indicate that a tumor antigen (TA)-specific mAb, such as cetuximab, can effectively trigger TA-specific cytotoxic T lymphocyte (CTL) responses. However, these effector CTLs are not fully effective, raising the possibility that inhibitory mechanisms limit the efficacy of cetuximab in the majority of patients. Blockade of these inhibitory mechanisms could restore anti-tumor activity and enhance cetuximab efficacy. However, the inhibitory mechanism(s) that are primarily responsible for limiting cetuximab efficacy remain unknown. A high frequency of peripheral blood T-lymphocytes (PBL) and tumor infiltrating T-lymphocytes (TIL) in multiple solid tumors, including HNSCC, express elevated levels of inhibitory receptors (so-called “checkpoints”), such as cytotoxic T lymphocyte antigen (CTLA-4) and programmed death-1 (PD-1), rendering them unresponsive to antigenic stimulation (exhaustion). Furthermore, CTLA-4+ regulatory T cells (Tregs), a potently suppressive sup- population of CD4+ T cells that produce TGF-β, are often present at increased frequencies and with enhanced suppressive capacity in tumors. Collectively, inhibitory receptors on CTL and Tregs are major barriers to effective anti-tumor T cell responses, which has been demonstrated by striking clinical responses to anti- CTLA-4 and anti-PD-1 antibodies. Our previous studies and preliminary data support a working model in which the generation of TA-specific CD8+ T cells triggered by cetuximab in the non-responder patient population occurs concurrently with increased inhibitory mechanisms (including TGF-β) that reduce the clinical response to cetuximab therapy. This project will take advantage of the availability of biospecimens from two novel UPCI clinical trials, which have either recently completed (UPCI 08-013, testing immune biomarkers in single-agent cetuximab treated patients)) or are ongoing (UPCI 12-084, combining cetuximab with anti-CTLA-4 mAb ipilimumab to inhibit Treg). We will determine whether inhibitory mechanisms are responsible for limiting anti-tumor activity induced in cetuximab-treated HNSCC patients and directly assess the impact of CTLA4+ Tregs in this new, ongoing clinical trial.