Targeting GITR for Tumor Immunotherapy

靶向 GITR 进行肿瘤免疫治疗

• 批准号: 7477999
• 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 2008-08-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477999
• 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; Immune system; 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(申请人提供)：抗癌的主动免疫治疗受到自身免疫耐受的阻碍，因为肿瘤细胞上表达的大部分抗原实际上是正常的自身抗原。我们使用激动型抗GITR(糖皮质激素诱导的肿瘤坏死因子受体)的单抗(MAb)来帮助克服这一障碍。GITR是一种肿瘤坏死因子受体家族成员，高表达于激活的效应器CD4+和CD8+T细胞以及Foxp3+调节性T细胞(Tregs)，Foxp3+调节性T细胞抑制自身(从而肿瘤)反应。使用激动剂mAb连接GITR可以诱导或加剧小鼠模型的自身免疫，证明了增强自我识别的能力。我们使用黑色素瘤小鼠模型发现，GITR结扎增强了对黑色素瘤自身抗原的免疫力，并可以加强对免疫原性低的肿瘤的主动和被动免疫治疗，局灶性色素沉着是唯一可观察到的自身免疫。然而，体内GITR结扎对荷瘤宿主的效应性和调节性T细胞的影响，以及对抗肿瘤作用的细胞亚群的影响还没有很好的确定。我们假设主动免疫期间的GITR信号直接共刺激肿瘤抗原特异性的CD4+和CD8+T细胞，导致增殖、效应功能和生存的增强。此外，我们认为，GITR结扎通过在肿瘤部位和引流淋巴结中禁用Tregs来进一步提高肿瘤免疫力。其具体目的是：1)研究GITR结扎对CD_4~+和CD_8~+效应T细胞的影响；2)研究GITR结扎对荷瘤宿主CD_4~+Foxp3+T细胞的影响；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(S)。 这些研究是相关的，因为免疫调节抗体(如抗CTLA4抗体)在晚期癌症患者中具有活性，而针对人类GITR的抗体已经在开发中。从机制上更好地了解抗GITR抗体对肿瘤免疫的影响，将使这一有前途的免疫治疗方法更合理地应用于临床。

项目成果

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• DOI: 10.1371/journal.pone.0199423
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Atreya CE;Kubo A;Borno HT;Rosenthal B;Campanella M;Rettger JP;Joseph G;Allen IE;Venook AP;Altschuler A;Dhruva A
• 通讯作者: Dhruva A