B7-H1/PD-1 modulation in cancer therapy

描述（由申请人提供）：癌症免疫治疗的前景是基于免疫系统的精细特异性，通过这种有效的机制可以消除目标细胞。然而，尽管有一些显著的成功案例，这种癌症治疗方式的发展进展仍未达到预期。解释基于T细胞的癌症免疫疗法局限性的主要见解来自抑制性共受体或称为免疫检查点的途径的发现，它们在正常生理环境和肿瘤疾病的背景下抑制T细胞的功能。最近的证据表明，肿瘤可能“篡夺”免疫检查点机制，从而形成一道屏障，阻止抗肿瘤免疫反应——包括内源性反应和由癌症疫苗等免疫疗法诱导的反应。动物癌症模型表明，阻断肿瘤细胞上的抑制分子与其在肿瘤特异性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”，导致肿瘤消退。因此，检查点抑制，单独应用或与疫苗联合应用，是增强抗肿瘤免疫的一种重要的新治疗方法。最有趣的抑制性共受体之一是PD-1，它在活化的T细胞上被诱导，并下调CD4+（“辅助”）和CD8+（“杀手”）亚群的关键功能。PD-1的主要配体是B7- h1 (PDL1)，它是B7家族成员，在激活时通常由几个白细胞亚群表达，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完全人源抗体阻断PD-1或B7-H1的临床试验提供了理论依据。值得注意的是，PD-1阻断治疗晚期难治性转移性实体瘤患者的I期临床试验中观察到客观肿瘤消退。因此，更好地了解PD-1和B7-H1的调控和功能，以及PD-1/B7-H1阻断对抗肿瘤免疫的影响至关重要。在目前的提议中，我们将验证B7-H1/PD-1抑制途径的调节可以通过改善肿瘤微环境和保护正在进行的T细胞活性来极大地提高癌症免疫治疗的疗效。本课题将基础科学与临床科学相结合，利用动物模型和人体体外系统实现以下目标：1)明确肿瘤细胞和其他细胞类型在肿瘤微环境中调控B7-H1表达的机制；2)表征影响T细胞PD-1表达的因素，特别是在疫苗诱导刺激的情况下；3)探讨B7-H1/PD-1阻断在肿瘤治疗中的临床作用的免疫学机制。综上所述，这些研究的结果将有助于PD-1/B7-H1阻断剂的合理临床开发，无论是单独使用还是联合使用，都可以用于癌症治疗。

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.