The OX40 receptor is transiently expressed on activated T cells and serves as a late co-stimulatory receptor.1,2
When OX40 is bound to its ligand, OX40L, which is typically expressed on activated antigen-presenting cells,3 an immune response may be augmented through several mechanisms that could include:
Activation of OX40 can also be achieved through the use of agonistic OX40-directed antibodies.6 Such treatment has the potential to enhance T-cell stimulation and promote potential tumor killing by the immune system.4 Agonistic OX40-directed antibodies can work as monotherapy or in combination with other immunotherapies to augment antitumor immune responses.1
MEDI0562 is a humanized mAb OX40 agonist, currently in clinical development to determine its antitumor effect where it may enhance T-cell stimulation and promote the immune system to kill tumors.6,7
TAKE A DEEPER LOOKat activating the OX40/OX40L axis
STAT3 (signal transducer and activator of transcription 3) is a transcription factor that plays a critical role in normal cell proliferation, differentiation, and apoptosis (programmed cell death). Constitutive activation of STAT3 has been identified in many types of tumors.8-10
AZD9150* is an investigational generation 2.5 antisense oligonucleotide that prevents STAT3 expression, thereby blocking tumor-intrinsic and tumor-extrinsic STAT3-mediated signaling. It is currently being evaluated for safety and efficacy in human clinical trials.7,11
Elevated extracellular levels of adenosine in the microenvironment of many solid tumors, driven by overexpression of CD73 (an ectoenzyme that catalyzes the conversion of AMP to adenosine) and by tissue breakdown and hypoxia, can exert potent immunosuppressive effects by binding of adenosine to the adenosine 2A receptor (A2AR) on antigen-presenting cell and lymphocytes, including T cells. This is known to suppress many aspects of anti-tumor immunity, including T-cell effector function.12
AZD4635 is an investigational small molecule A2AR antagonist that selectively binds to A2AR. A2AR antagonists help to overcome adenosine-mediated immunosuppression in a number of solid tumor model systems.7,12
AZD4635 is currently being evaluated as a monotherapy, and in combination with durvalumab, for safety and efficacy in human clinical trials.7
CD73 or ecto-5’-nucleotidase is a cell surface enzyme expressed on endothelial cells, lymphoid cells, and myeloid cells, including antigen-presenting cells. It catalyzes the conversion of extracellular adenosine monophosphate (AMP) to the nucleoside adenosine.13,14
Overexpression of CD73 and elevated extracellular levels of adenosine in the microenvironments of many solid tumors are known to exert potent immunosuppressive effects by binding of adenosine to adenosine receptors on antigen-presenting cells and lymphocytes including T cells. This is known to suppress many aspects of antitumor immunity.13,15-17
MEDI9447 is an investigational human IgG1λ monoclonal antibody that selectively binds to and inhibits the ectonucleotidase activity of CD73. Results from preclinical studies suggest that MEDI9447 may help to overcome adenosine-mediated immunosuppression in a number of solid tumor model systems. The molecule is currently being evaluated for safety and efficacy in human clinical trials.7,18
GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) is a surface receptor expressed on regulatory T cells (Tregs) and on activated effector T cells. Interaction of GITR and its ligand (GITR-L) enhances the proliferation and activation of T cells in response to antigen.19,20
Activation of GITR by agonistic anti-GITR antibodies stimulates effector T-cell expansion and cytokine production, which has been reported to induce antitumor immune responses and regression of tumors.19,20
MEDI1873 is an investigational human GITR-L fusion protein that binds to GITR and drives T-cell activation signals. In addition to stimulating T-cell expansion and cytokine production, the molecule has the potential to deplete Tregs through Fc-mediated effector functions.21 This molecule is currently being evaluated for safety and efficacy in human clinical trials.7
NKG2A is an immune checkpoint inhibitor receptor that is primarily expressed on tumor infiltrating innate immune effector NK cells, as well as on some CD8+ T cells.22-24 Its natural ligand, HLA-E, is highly expressed on many solid and hematologic tumors.25 Binding of tumor-associated HLA-E to NKG2A inhibits NK cell and CD8 T-cell activation and ablates NK cell and CD8 T-cell-mediated antitumor killing.26
Monalizumab* (IPH2201) is a first-in-class, investigational anti-NKG2A antibody that binds to NKG2A on NK cells and some CD8+ T cells, and helps block the inhibitory interactions between tumor-associated HLA-E and the NKG2A receptor. This, in turn, may enhance innate immune antitumor responses.23
This molecule is being evaluated in human clinical trials as a potential treatment for solid tumors and hematologic malignancies.7,23
Stimulation of toll-like receptor (TLR) 7 and TLR8 on dendritic cells induces a local tumor immune response characterized by secretion of Th1 proinflammatory cytokines and chemokines and activation of NK cells and tumor-specific CD8 cytotoxic T cells.27
MEDI9197 (formerly 3M-052*) is an investigational imidazoquinoline-like TLR7/8 agonist designed with a lipid tail that, when injected, helps retain the molecule within the tumor.28,29
Preclinical studies suggest that MEDI9197 may induce a prolonged localized and systemic cell mediated, anti-tumor immune response in solid tumors, without systemic cytokine-storm like effects, after intra-tumor delivery.7,29
This molecule is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials.7
*Licensed from 3M Corporation.
CXCR2 is a chemokine receptor that binds its chemokine ligands CXCL1 and CXCL8 and is found on myeloid-derived suppressor cells (MDSCs)—a class of immature myeloid cells that originate in the bone marrow.30,31
During tumorigenesis, CXCR2+ MDSCs migrate via the vasculature in response to increased ligand production by the tumor and localize in tumor microenvironments. There, they contribute to immune evasion by secreting cytokines that modify the tumor microenvironment, reducing T-cell trafficking and activation, and dampening NK cell activity and promoting regulatory T-cell (Treg) expansion.31,32
AZD5069 is an investigational selective CXCR2 antagonist that inhibits the migration of CXCR2+ MDSCs to tumor microenvironments and may enhance immune-mediated tumor killing. It is currently being evaluated for safety and efficacy in human clinical trials.7,32
Safety and efficacy of the agent under investigation have not been established. Investigational agents are not approved by the US or any other regulatory agency for the uses under investigation.
The information provided here includes details of products that are still in development and is for personal information purposes only. AstraZeneca does not, under any circumstances, promote its products for off-label, unapproved uses.
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Up-regulation of inhibitory natural killer receptors on CD94/N KG2A with suppressed intracellular perforin expression of tumor-infiltrating CD8+ T lymphocytes in human cervical carcinoma. Cancer Res. 2005;1:2921-2929. 25. Talebian Yazdi M, van Riet S, van Schadewijk A et al. The positive prognostic effect of stromal CD8+ tumor-infiltrating T cells is restrained by the expression of HLA-E in non-small cell lung carcinoma. Oncotarget. 2015;7(3):3477-3488. 26. Pace E, Di Sano C, Ferraro M et al. Altered CD94/N KG2A and perforin expression reduce the cytotoxic activity in malignant pleural effusions. Eur J Cancer. 2011;47:296-304. 27. Gorden K, Gorski K, Gibson S et al. Synthetic TLR agonists reveal functional difference between human TLR7 and TLR8. J Immunol. 2005;174:1259-1268. 28. Mullins SR, Vogel K, Vasilakos J et al. 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Published online June 19, 2014. 2014;7(24). doi:10.1038/scibx.2014.693.