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OX40 Agonists: Boosting Cancer Immunotherapy

Following our recent post covering the Tumor Necrosis Factor Superfamily of Ligands and Receptors, we’re going to take a closer look at specific family members important in immuno-oncology. First up is the OX40 receptor and its binding partner OX40-Ligand (OX40L).

Important Targets in T Cell Co-Stimulation

OX40 is now at the forefront of the field which has been called “T cell co-stimulation”. Immune co-stimulators work by providing the signal that promotes the expansion and proliferation of killer CD8 and helper CD4 T cells.

While immune checkpoint therapies are “releasing the brakes,” co-stimulators are “stepping on the gas.” Both mechanisms are required for a robust immune system response.

Receptor and Ligand Characteristic of the TNFR Superfamily

OX40 (also known as CD134, ACT35, and TNFRSF4) is a 50kD type 1 transmembrane glycoprotein. The extracellular N-terminal portion of OX40 is 191 amino acids, containing three complete and one truncated cysteine-rich domains (CRDs) which are characteristic of the Tumor Necrosis Factor Receptor (TNFR) superfamily. The intracellular region consists of 36 amino acids.

OX40L (also known as gp34, CD252, and TNFSF4) is a 34kD type II transmembrane glycoprotein. It is expressed as a trimer and has a TNF homology domain; therefore, it is structurally similar to other molecules of the TNF superfamily and has some sequence homology.

OX40 and OX40L Genes Clustered with Other Family Members

The gene for OX40 is clustered on human chromosome 1 (mouse chromosome 4) with several other TNFR family molecules e.g. TNFR2, 4-1BB, HVEM, CD30, GITR, and DR3. The OX40L gene is on human and mouse chromosome 1, clustered with genes for two other TNF family members, FasL and GITRL.

OX40 Ligand Binding Modulates T Cell Activation and T Cell Effector Function

The OX40 receptor is expressed primarily on CD8+ T cells, NK cells, NKT cells, and neutrophils. OX40L is expressed on dendritic cells (DCs), B cells, macrophages, and at sites of inflammation (e.g. activated endothelium).

OX40 is a co-stimulatory receptor not constitutively expressed on resting naïve T cells, instead it serves as a secondary co-stimulatory immune checkpoint molecule. OX40L is also not expressed on resting antigen presenting cells, but is present following their activation.

Binding of OX40 to its ligand modulates T cell activation and T cell effector function.

Targeting OX40 in Preclinical Studies: Improved Tumor Free Survival and Immune Memory Response

Preclinical studies have shown that using anti-OX40 mAbs and OX40L-Fc fusion proteins can increase antitumor immunity and improve tumor free survival (1,2). OX40 dependent antitumor immunity required the expansion of CD8 and CD4 T cells, with a proportion of mice showing evidence of a strong memory sufficient to provide resistance upon tumor re-challenge (3,4).

Treg Cell Effects – Both Depletion and Expansion Observed

Preclinical studies have also shown that OX40 agonists might exert their anticancer activity by depleting the number of FoxP3+ regulatory T (Treg) cells, which express high levels of OX40.

In mice, OX40 is constitutively expressed on Treg cells, which is in contrast to humans where expression is induced - there is low/absent expression on peripheral Treg cells, but higher OX40 expression on human Treg cells isolated from sites of inflammation (e.g. tumors).

However, others have observed Treg cell expansion (5,6), suggesting that anti-OX40 can push Treg cells in both directions, depending upon the context of stimulation and the cytokine environment.

Clinical Trials Ongoing Including Combination Therapy

Recently, Phase I monotherapy studies [NCT01644968] have been conducted with an OX40 agonist (9B12, mouse monoclonal anti-OX40 antibody) in patients with metastatic solid tumors. Promising results were observed, showing a strong bioactivity of the compound, although no antitumor responses were seen (7). 12 out of 30 patients showed regression of at least one metastatic lesion, and the agent was well tolerated with mild to moderate side effects.

In order to increase anti-OX40 effect, a variety of combinatory therapy strategies are being investigated.

Currently, agonistic OX40 monoclonal antibodies (e.g. MOXR0916, PF-04518600, MEDI0562, MEDI6469, and MEDI6383) are being evaluated in several Phase I/II clinical trials either as monotherapy or in combination with other immunomodulating agents:

  • Durvalumab (anti-PD-L1 antibody) [NCT02221960]
  • Tremelimumab (anti-CLTA-4 antibody)/rituximab (anti-CD20 antibody) [NCT02205333]
  • utomilumab (anti-CD137 antibody) [NCT02315066]
  • atezolizumab (anti-PD-L1 antibody)/bevacizumab (anti-VEGF-A antibody) [NCT02410512] (8).

OX40 Combination Regimens Expanding Immunotherapy Benefits

The use of OX40 targeted co-stimulatory agonistic antibodies with other anticancer approaches, including immunotherapy, are promising approaches to overcoming the suppressive tumor microenvironment and expanding the cohort of patients that benefit from immune mediated cancer therapies.

References and Further Reading:

  1. Linch SN et al. OX40 Agonists and Combination Immunotherapy: Putting the Pedal to the Metal. Front Oncol. 2015;5: 34.
  2. Jensen SM et al. Signaling through OX40 enhances antitumor immunity. Semin Oncol. 2010;37(5): 524-32.
  3. Gough MJ et al. Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice. J Immunother. 2010;33(8): 798-809.
  4. Song A et al. Cooperation between CD4 and CD8 T cells for anti-tumor activity is enhanced by OX40 signals. Eur J Immunol. 2007;37(5): 1224-32.
  5. Ruby CE et al. Cutting Edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. J Immunol. 2009;183(8): 4853-7.
  6. Xiao X et al. New insights on OX40 in the control of T cell immunity and immune tolerance in vivo. J Immunol. 2012;188(2): 892-901.
  7. Curti BD et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 2013;73(24): 7189-7198.
  8. Aspeslagh S et al. Rationale for anti-OX40 cancer immunotherapy. Eur J Cancer. 2016;52: 50-66.

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