B7-H1/PD-1 modulation in cancer therapy

描述（由申请人提供）：癌症免疫疗法的前景是基于免疫系统的精确特异性，通过免疫系统，一种有效的机制可以消除靶细胞。然而，尽管有一些值得注意的成功例子，但开发这种形式的癌症治疗的进展低于预期。解释基于T细胞的癌症免疫疗法的局限性的主要见解来自于被称为免疫检查点的抑制性共受体或途径的发现，其在正常生理环境中以及在肿瘤疾病的背景下抑制T细胞功能。最近的证据表明，肿瘤可能“篡夺”免疫检查点机制，以建立对抗抗肿瘤免疫反应的屏障-包括内源性反应和由免疫疗法（如癌症疫苗）诱导的反应。动物癌症模型表明，阻断肿瘤细胞上的抑制性分子与肿瘤特异性T细胞上的共受体的相互作用可以“释放抗肿瘤免疫的刹车”并导致肿瘤消退。因此，单独或与疫苗组合应用的检查点抑制代表了用于增强抗肿瘤免疫的重要的新治疗方法。最令人感兴趣的抑制性共受体之一是PD-1，其在活化的T细胞上诱导并下调CD 4+（“辅助”）和CD 8+（“杀伤”）亚群中的关键功能。PD-1的主要配体是B7-H1（PDL 1），B7家族成员通常在活化后由几个白细胞亚群表达，并在许多人类癌症中异常表达。这些发现强调了PD-1/B7-H1相互作用可能抑制抗肿瘤免疫的多种机制，为在癌症患者中使用阻断PD-1或B7-H1的完全人源抗体进行临床试验提供了依据。值得注意的是，在晚期难治性转移性实体瘤患者中进行的PD-1阻断的第一项I期试验中观察到客观肿瘤消退。现在，更好地了解PD-1和B7-H1的调节和功能，以及识别PD-1/B7-H1阻断对抗肿瘤免疫的影响至关重要。在目前的提案中，我们将检验这样的假设，即B7-H1/PD-1抑制通路的调节可以通过改善肿瘤微环境和保护持续的T细胞活性来大大增强癌症免疫治疗的功效。目前的提案整合了基础和临床科学，并将使用动物模型和人类体外系统来实现以下目标：1）确定肿瘤细胞和肿瘤微环境中其他细胞类型调节B7-H1表达的机制; 2）表征影响T细胞表达PD-1的因素，特别是在疫苗诱导的刺激下;以及3）表征B7-H1/PD-1阻断剂在癌症治疗中的临床效果的免疫学机制。综上所述，这些研究的结果将使PD-1/B7-H1阻断剂（单独或联合方案）在癌症治疗中的合理临床开发成为可能。 公共卫生相关性：虽然在科学水平上已经取得了显着的进展，在了解管理免疫系统对抗癌症的活动的调节过程中，这些发现的临床应用，以开发有效的癌症疗法将需要更详细的知识的分子和途径。我们的目标是：1）阐明癌细胞表达的免疫调节分子B7-H1和活化的抗肿瘤T淋巴细胞表达的PD-1之间的相互作用如何支持癌症进展; 2）利用这些知识开发基于阻断B7-H1/PD-1连接的有效癌症免疫疗法。

DESCRIPTION (provided by applicant): The promise of cancer immunotherapy is based upon the exquisite specificity of the immune system, through which a potent machinery can eliminate targeted cells. However, despite some notable examples of success, progress in developing this form of cancer therapy has fallen short of expectations. Major insights explaining the limitations of T cell-based cancer immunotherapies have come from the discovery of inhibitory co-receptors or pathways termed immune checkpoints, which restrain T cell functions in normal physiologic settings as well as in the context of neoplastic disease. Recent evidence suggests that tumors may "usurp" immunological checkpoint mechanisms to create a barrier against antitumor immune responses - including endogenous responses and those induced by immunotherapies such as cancer vaccines. Animal cancer models demonstrate that blocking the interaction of inhibitory molecules on tumor cells with their co-receptors on tumor-specific T cells can "release the brakes" on antitumor immunity and cause tumor regression. Thus, checkpoint inhibition, applied alone or in combination with vaccines, represents an important new therapeutic approach for enhancing antitumor immunity. One of the most interesting inhibitory co-receptors is PD-1, that is induced on activated T cells and down-modulates critical functions in both CD4+ ("helper") and CD8+ ("killer") subsets. The major ligand for PD-1 is B7-H1 (PDL1), a B7 family member normally expressed by several leukocyte subsets upon activation, and aberrantly expressed in many human cancers. These findings, highlighting multiple mechanisms by which PD-1/B7-H1 interactions may inhibit antitumor immunity, have provided a rationale for clinical trials in cancer patients using fully human antibodies blocking PD-1 or B7-H1. Notably, objective tumor regressions were observed in the first phase I trial of PD-1 blockade in patients with advanced treatment-refractory metastatic solid tumors. It is now critically important to better understand the regulation and function of PD-1 and B7-H1, and to discern the effects of PD-1/B7-H1 blockade on antitumor immunity. In current proposal, we will test hypothesis that modulation of B7-H1/PD-1 inhibitory pathway could vastly enhance efficacy of cancer immunotherapy by improving tumor microenvironment and protecting ongoing T cell activity. The current proposal integrates basic and clinical science, and will use animal models and human in vitro systems to achieve the following aims: 1) To define mechanisms regulating B7-H1 expression by tumor cells and other cell types in the tumor microenvironment; 2) To characterize factors influencing PD-1 expression by T cells, particularly in the context of vaccine-induced stimulation; and 3) To characterize immunological mechanisms underlying the clinical effects of B7-H1/PD-1 blockade in cancer therapy. Taken together, results from these studies will enable the rational clinical development of PD-1/B7-H1 blockade, alone or in combinatorial regimens, in cancer therapy. PUBLIC HEALTH RELEVANCE: Although remarkable progress has been made on a scientific level in understanding regulatory processes governing the activity of the immune system against cancer, the clinical application of these findings to develop effective cancer therapies will require a more detailed knowledge of the molecules and pathways involved. Our objectives are 1) to elucidate how interactions of the immune regulatory molecules B7-H1, expressed by cancer cells, and PD-1, expressed by activated antitumor T lymphocytes, support cancer progression; and 2) to use this knowledge to develop effective cancer immunotherapies based on blockade of B7-H1/PD-1 ligation.