GITR是肿瘤坏死因子受体超家族(TNFRSF)中的一个共刺激分子，在增强新生免疫应答中起着关键作用，活化的T细胞上调表达，Tregs上组成性表达，在NK细胞上低表达。配体与GITR的结合可调节NFκB和MAPK通路。GITR信号通路导致T细胞的激活、增殖、存活和抑制Treg的抑制活性。
Eur. J. Cancer. 67, 1–10 (2016).对于GITR激动剂单药，各大药企都展示和浓厚的的兴趣，比如MSD(MK-4166, MK-1248), BMS (BMS-986156),Amgen(AMG-228), MedImmune(MEDI1873)，国内恒瑞医药（SHR-1705），信达生物（IBI102）等。已经发表的临床研究数据显示，抗GITR抗体具有可接受的耐受性，虽然可以介导Treg的清除，但其治疗效果有限的（参考文献2-4）。可能原因是：不能有效的介导GITR聚簇（clustering），因而不能有效激活T细胞并促进其增殖。JAMA Oncol. 6, 100–107 (2019).在MSD进行的GITR激动剂(MK-4166, MK-1248)联用K药的临床中，看到了一些CR和PR的数据。近日，Nature Cancer发表了由多家Bigpharma和Biotech合作的GITR激动剂Xanti-PD-1双抗，参与的单位包括：AbbVie，Calico Labs, Seattle Genetics, Bristol Myers Squibb, Bolt Biotherapeutics, Inc., Sanofi, Oxford Biotherapeutics, Good Therapeutics, Inc.，足见业界的热情。1. anti-PD1依赖性GITR聚簇是起效的关键2. anti-PD1XGTIR-L抑制人源化小鼠模型中MC-38肿瘤生长3. anti-PD1XGTIR-L促进效应T细胞体内分裂，强于anti-PD-1 和GITR-L联合用药。
刺激PBMC释放更高水平的IL-2、IFN-γ、TNF
参考资料
1.Knee, D. A., Hewes, B. & Brogdon, J. L. Rationale for anti-GITR cancer
immunotherapy. Eur. J. Cancer. 67, 1–10 (2016).
2.Zappasodi, R. et al. Rational design of anti-GITR-based combination
immunotherapy. Nat. Med. 25, 759–766 (2019).
3.Papadopoulos, K. P. et al. Phase 1 study of MK-4166, an anti-human
glucocorticoid-induced tumor necrosis factor receptor (GITR) antibody, as
monotherapy or with pembrolizumab in patients with advanced solid tumors.
J. Clin. Oncol. 37, 9509 (2019).
4.Heinhuis, K. M. et al. Safety, tolerability, and potential clinical activity of a
glucocorticoid-Induced TNF receptor–related protein agonist alone or in
combination with nivolumab for patients with advanced solid tumors. JAMA
Oncol. 6, 100–107 (2019).
5.Sarah Chan et al, An anti-PD-1–GITR-L bispecific agonist induces GITR clustering-mediated T cell activation for cancer immunotherapy,Nat Cancer . 2022 Mar 7
