Targeting GITR for Tumor Immunotherapy

描述（由申请人提供）：针对癌症的主动免疫疗法受到自身免疫耐受的阻碍，因为肿瘤细胞上表达的大多数抗原实际上是正常的自身抗原。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）来帮助克服这种障碍。GITR是一种TNF受体家族成员，在活化的效应CD 4+和CD 8 + T细胞以及Foxp 3+调节性T细胞（TCRs）上高度表达，其抑制自身（因此抑制肿瘤）反应性。使用激动剂mAb连接GITR可以诱导或加剧小鼠模型中的自身免疫，证明了增强自我识别的能力。我们已经发现，使用黑素瘤小鼠模型，GITR连接增强了对黑素瘤自身抗原的免疫力，并且可以增强针对免疫原性差的肿瘤的主动和被动免疫疗法，其中局灶性色素减退是唯一可观察到的自身免疫。然而，体内GITR连接对荷瘤宿主中的效应T细胞和调节T细胞以及负责抗肿瘤作用的细胞亚群的影响尚未明确。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CD 4+和CD 8 + T细胞，导致增殖、效应子功能和存活率增强。此外，我们提出GITR结扎通过使肿瘤部位和引流淋巴结中的TdR失能来进一步提高肿瘤免疫力。具体目标是：1）表征GITR连接对CD 4+和CD 8+效应T细胞的作用; 2）研究GITR连接对荷瘤宿主中CD 4 + Foxp 3 + T细胞的作用;和3）使用GITR阳性或GITR缺陷细胞的体内转移，确定抗GITR mAb靶向以产生增强的肿瘤免疫的淋巴细胞亚群。 这些研究是相关的，因为免疫调节抗体（如抗CTLA 4抗体）在晚期癌症患者中具有活性，并且靶向人GITR的抗体已经在开发中。获得抗GITR抗体对肿瘤免疫的作用的更大机制理解将允许将这种有前途的免疫学方法更合理地转化为临床。

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.