3.2 OX40 (CD134)
OX40 (also known as CD134 or or TNFRSF4) is a co-stimulatory receptor expressed primarily on activated T cells ( regulatory T phenotypes constitutively and by effector T cells after activation), belonging to the tumor necrosis factor receptor (TNFR) superfamily [275]. Its interaction with its ligand, OX40 ligand (OX40L), which is expressed on antigen-presenting cells (APCs) and other cell types (vascular endothelial cells, mast cells,  and some T cells.), plays a critical role in regulating immune responses [275, 292].
Upon binding to OX40L, OX40 signaling delivers potent co-stimulatory signals to T cells. These signals promote T cell activation, expansion, survival, and differentiation into effector and memory T cells. OX40 signaling also enhances the production of cytokines such as interleukin-2 (IL-2), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), which are crucial for orchestrating effective immune responses against pathogens and tumors [292, 293].
Agonistic antibodies or other agents (OX40L-Fc fusion proteins, transfected DCs with OX40L mRNA, and tumor cells engineered to express OX40L on their surface, immune-activating recombinant modified vaccinia virus Ankara  (rMVA, MVA∆E5R-Flt3L-OX40L)), that activate OX40 have shown encouraging result [275, 294, 295, 296] These agents aim to amplify T cell responses within the TME, where immune responses are often suppressed. By enhancing T cell activation and function, OX40 agonists can potentially overcome immune evasion mechanisms employed by tumors and improve the efficacy of anti-cancer immune responses. Fully human IgG1 agonist mAb developed include INCAGN01949, IBI101, GSK3174998 and BMS-986178. [294, 297, 298, 299]. Fully human IgG2 agonist Ab developed include Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) [300]. mRNA-2752 is a lipid nanoparticle encapsulating mRNAs encoding human OX40L, IL-36γ and IL-23 [301]. MEDI6383 is a human OX40L IgG4P Fc fusion protein. SL-279252 is a dual-sided Fc fusion protein PD1-Fc-OX40L [275]. In a study by Campos Carrascosa et al., treatment with an Fc-engineered αOX40 antibody (αOX40_v12), which has selectively enhanced FcγRIIB affinity, stimulated the expansion of CD4+ and CD8+ TILs in vitro, as well as the secretion of cytokines and chemokines [302]. A study by Reuter et al. demonstrated that, OX40L transgenic Ewing sarcoma cells showed enhanced immune stimulation against Ewing sarcoma cells in combination with IL-2 and stimulation of CD137 [303].
Monotherapy and combination therapies involving OX40 agonists with other immunotherapies, such as ICIs (e.g., anti-PD-1, anti-CTLA-4 antibodies), are actively being explored. Phase I /II completed clinical trials include, [NCT02274155, MEDI6469] [NCT02219724, MOXR0916] [NCT01644968, 9B12] [NCT03894618, SL-279252] [NCT01303705, MEDI6469 in combination with Cyclophosphamide, radiation ] [NCT03390296, PF-04518600 in combination with Azacitadine/ Avelumab/ Glasdegib/ Gemtuzumab/ Ozogamicin] [NCT02315066, PF-04518600 in combination with Utomilumab (4-1BB agonist mAb)] [NCT02410512, MOXR0916 in combination with anti-PD-L1]. Active clinical trials (currently recruiting/not recruiting) include [NCT03336606, MEDI0562] [NCT05105971, BAT6026] [NCT04714983, DNX-2440 (intra-tumoral injection)] [NCT05229601, HFB301001] [NCT04730843, ES102] [NCT04648202, FS120 (bispecific antibody, OX40/CD137)] [NCT05263180, EMB-09 (bispecific antibody, OX40 and PD-L1)] [NCT01862900, MEDI6469 in combination with stereotactic body radiation] [NCT03831295, BMS 986178 in combination with TLR9 agonist SD-101] [NCT03410901, BMS 986178 in combination with TLR9 agonist SD-101, radiation] [NCT03217747, PF-04518600 in combination with Avelumab, utomilumab, ivuxolimab, radiation] [NCT03971409, PF-04518600 in combination with Avelumab, binimetinib, utomilumab, liposomal doxorubicin, or sacituzumab govitecan] [NCT04198766, INBRX-106 in combination with Pembrolizumab] [NCT04991506, ES102 in combination with Toripalimab ] [NCT04215978, BGB-A445 in combination with Tislelizumab] [NCT05109650, BAT6026 in combination with ati PD-1] For Recommended phase 2 dosing and complete response rate, also clinical trial is being done (NCT03636503)