B7-H1/PD-1 modulation in cancer therapy

癌症治疗中的 B7-H1/PD-1 调节

• 批准号: 8676698
• 负责人: Lieping Chen
• 金额: $ 44.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-21 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676698
• 关键词: Animal Cancer Model; Animal Model; Antibodies; Antigen-Presenting Cells; B7-DC antigen; Basic Science; Binding; Biopsy; Blocking Antibodies; CD80 gene; CD8B1 gene; Cancer Model; Cancer Patient; Cancer Vaccines; Cell Culture System; Cell physiology; Cells; Clinical; Clinical Sciences; Clinical Trials; Complex; Dendritic Cells; Development; Disease; Family member; Human; Immune; Immune response; Immune system; Immunity; Immunoglobulins; Immunotherapy; In Vitro; Interferon Type II; Knowledge; Leukocytes; Ligands; Ligation; Malignant Neoplasms; Pathway interactions; Patients; Pattern recognition receptor; Pharmacodynamics; Phase I Clinical Trials; Physiological; Process; Prostate; Refractory; Regimen; Regulation; Renal carcinoma; Role; Signal Transduction; Solid Neoplasm; Specificity; System; T cell regulation; T-Lymphocyte; Testing; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Vaccines; Viral Tumor Antigens; base; cancer cell; cancer immunotherapy; cancer therapy; cell type; clinical application; clinical effect; combinatorial; cytokine; expectation; falls; immunoregulation; improved; insight; interest; melanoma; member; neoplastic; neoplastic cell; novel therapeutic intervention; prostate cancer model; receptor; response; success; tumor; tumor microenvironment; tumor progression

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.

描述（由申请人提供）：癌症免疫疗法的承诺基于免疫系统的精致特异性，有效的机械可以消除靶向细胞。然而，尽管成功的例子有一些显着的例子，但发展这种形式的癌症治疗的进展仍未达到预期。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发现抑制性共受体或称为免疫检查点的途径，这些途径抑制了在正常生理环境中的T细胞功能以及在肿瘤疾病的背景下。最近的证据表明，肿瘤可能会“篡夺”免疫检查点机制，以造成抵抗抗肿瘤免疫反应的障碍 - 包括内源性反应和由癌症疫苗等免疫疗法引起的障碍。动物癌模型表明，在肿瘤特异性T细胞上阻止抑制性分子在肿瘤细胞上的相互作用与其受体受体可以“释放抗肿瘤免疫”并引起肿瘤退化。因此，单独应用或与疫苗结合使用的检查点抑制作用代表了增强抗肿瘤免疫力的重要新治疗方法。最有趣的抑制性共受体是PD-1，它在激活的T细胞上诱导，并在CD4+（“ Helper”）和CD8+（“杀手”）子集中降低了关键功能。 PD-1的主要配体是B7-H1（PDL1），这是一种B7家族成员，通常在激活后由几个白细胞亚群表达，并且在许多人类癌症中异常表达。这些发现突出了多种机制PD-1/B7-H1相互作用可能抑制抗肿瘤免疫，为使用完全人类抗体阻断PD-1或B7-H1的癌症患者的临床试验提供了一个理由。值得注意的是，在患有晚期治疗 - 不良转移性实体瘤患者的PD-1封锁的第一阶段试验中，观察到了客观肿瘤的回归。现在，更好地了解PD-1和B7-H1的调节和功能至关重要，并辨别PD-1/B7-H1阻断对抗肿瘤免疫的影响。在目前的提案中，我们将检验假设，即通过改善肿瘤微环境和保护持续的T细胞活性，可以大大提高B7-H1/PD-1抑制途径的调节可以极大地提高癌症免疫疗法的功效。当前的提案整合了基本和临床科学，并将使用动物模型和人类体外系统来实现以下目的：1）定义肿瘤微环境中肿瘤细胞和其他细胞类型来调节B7-H1表达的机制； 2）表征影响T细胞PD-1表达的因素，特别是在疫苗诱导的刺激的情况下； 3）表征B7-H1/PD-1阻断癌症治疗中临床作用的背后的免疫机制。综上所述，这些研究的结果将使PD-1/B7-H1阻断的合理临床发展（单独或组合方案）在癌症治疗中。