Targeting GITR for Tumor Immunotherapy

靶向 GITR 进行肿瘤免疫治疗

• 批准号: 7246389
• 负责人: ADAM D COHEN
• 金额: $ 13.82万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7246389
• 关键词: Active Immunization; Active Immunotherapy; Advanced Malignant Neoplasm; Agonist; Animal Model; Antibodies; Antigens; Autoantigens; Autoimmunity; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cell physiology; Cells; Clinic; DNA; Development; Equilibrium; Family member; Glucocorticoids; Goals; Human; Hypopigmentation; Immune; Immune Tolerance; Immunity; Immunologics; Immunotherapeutic agent; Immunotherapy; Infiltration; Ligation; Lymphocyte Subset; Malignant Neoplasms; Modeling; Monoclonal Antibodies; Mus; Mutate; Passive Immunotherapy; Patients; Personal Satisfaction; Pre-Clinical Model; Research Personnel; Signal Transduction; Site; System; T-Lymphocyte; Testing; Translations; Tumor Antigens; Tumor Immunity; Tumor Necrosis Factor Receptor; Vaccination; Vaccines; cancer immunotherapy; clinically relevant; design; immunogenic; improved; in vivo; intravital microscopy; killings; lymph nodes; melanoma; mouse model; neoplastic cell; pathogen; programs; response; success; trafficking; tumor; tumor growth; two-photon

DESCRIPTION (provided by applicant): Active immunotherapy against cancer is hindered by immune tolerance to self, as the majority of antigens expressed on tumor cells are in fact normal self antigens. We have investigated using an agonist monoclonal antibody (mAb) against GITR (glucocorticoid-induced tumor necrosis factor (TNF) receptor) to help overcome this barrier. GITR is a TNF receptor family member expressed highly on activated effector CD4+ and CD8+ T cells, as well as on Foxp3+ regulatory T cells (Tregs) which suppress self- (and therefore tumor-) reactivity. Ligating GITR using an agonist mAb can induce or exacerbate autoimmunity in mouse models, demonstrating the capacity for enhanced self-recognition. We have found using a melanoma mouse model that GITR ligation enhances immunity to melanoma self antigens, and can augment both active and passive immunotherapy against a poorly immunogenic tumor, with focal hypopigmentation as the only observable autoimmunity. However, the consequences of in vivo GITR ligation on effector and regulatory T cells in a tumor-bearing host, as well as the cellular subpopulations responsible for the anti-tumor effects, have not been well-defined. We hypothesize that GITR signaling during active immunization directly co-stimulates tumor antigen-specific CD4+ and CD8+ T cells, leading to enhanced proliferation, effector function and survival. In addition, we propose that GITR ligation further improves tumor immunity by disabling Tregs at the tumor site and in draining lymph nodes. The specific aims are to: 1) Characterize the effects of GITR ligation on CD4+ and CD8+ effector T cells; 2) Investigate the effects of GITR ligation on CD4+Foxp3+ Tregs in tumor-bearing hosts; and 3) Determine the lymphocyte subpopulation(s) that anti-GITR mAb targets to generate enhanced tumor immunity, using in vivo transfer of GITR-positive or GITR-deficient cells. These studies are relevant because immune-modulating antibodies (such as anti-CTLA4 antibody) have activity in patients with advanced cancer, and antibodies targeting human GITR are already in development. Gaining greater mechanistic understanding of the effects of anti-GITR antibody on tumor immunity will allow for more rational translation of this promising immunotherapeutic approach to the clinic.

描述（由申请人提供）：肿瘤细胞上表达的大多数抗原实际上是正常的自身抗原，因此对自身的免疫耐受阻碍了主动免疫治疗。我们已经研究了使用针对GITR（糖皮质激素诱导的肿瘤坏死因子（TNF）受体）的激动剂单克隆抗体（mAb）来帮助克服这一屏障。GITR是TNF受体家族成员，在活化效应CD4+和CD8+ T细胞以及Foxp3+调节性T细胞（Tregs）上高度表达，抑制自身（从而抑制肿瘤）反应性。在小鼠模型中，使用激动剂mAb连接GITR可以诱导或加剧自身免疫，显示出增强自我识别的能力。我们在黑素瘤小鼠模型中发现，GITR结扎增强了对黑素瘤自身抗原的免疫，并且可以增强对免疫原性差的肿瘤的主动和被动免疫治疗，局灶性色素减退是唯一可观察到的自身免疫。然而，体内GITR连接对肿瘤宿主中效应T细胞和调节性T细胞的影响，以及负责抗肿瘤作用的细胞亚群，尚未明确定义。我们假设主动免疫过程中的GITR信号直接共同刺激肿瘤抗原特异性CD4+和CD8+ T细胞，从而增强增殖、效应功能和存活。此外，我们提出GITR结扎通过使肿瘤部位的Tregs和引流淋巴结丧失功能进一步提高肿瘤免疫。具体目的是：1)表征GITR结扎对CD4+和CD8+效应T细胞的影响；2)探讨GITR结扎对荷瘤宿主CD4+Foxp3+ Tregs的影响；3)通过体内转移gitr阳性或gitr缺陷细胞，确定抗gitr单抗靶向产生增强肿瘤免疫的淋巴细胞亚群。