In Part 1 we introduced the evolutionarily related TNF receptor superfamily receptors OX40, 4-1BB, CD27 and GITR (link). All of there receptors are being targeted for cancer therapy due to their ability to stimulate CD4+ and/or CD8+ T cells while potentially shutting down T regulatory cells (Tregs).
The receptor OX40 (CD134) is expressed primarily on CD8+ T-cells, NK cells, NKT cells, and neutrophils. OX40L is expressed on dendritic cells (DCs), B-cells, and macrophages, and at sites of inflammation (e.g. activated endothelium). The expression pattern suggests a critical role for OX40L/OX40 is supporting immune responses. Additional information on the role of this pathway comes from the analyses of expression kinetics upon immune cell activation. OX40 is transiently upregulated on activated CD4+ and CD8+ T cells after engagement of the T cell receptor (TCR). The window of expression is from ~12 hours through ~96 hours, after which the receptor is downregulated. This receptor therefore functions to support the survival and expansion of already activated effector T cells. Importantly, OX40 agonism also reactivates the memory T cell population.
Clinical trials using a mouse anti-OX40 agonist antibody were spurred on by impressive results in preclinical tumor models, both as single agent therapy (in immunogenic tumors) and in combination with chemotherapy and irradiation. Various other combination therapies have since been tested preclinically, and that work is continuing. Early clinical trials with anti-OX40 agonist mAb show that the therapeutic is well tolerated, and have provided evidence of immune system stimulation and modest signs of clinical activity.
The latest clinical update I can find is from the SITC meeting in November 2013 (link). In a poster entitled “Phase I/II clinical trial of anti-OX40, radiation and cyclophosphamide in patients with prostate cancer: immunological analysis”, Andrew Weinberg’s group from the Providence Cancer Center, Portland, OR report out as follows. The Phase 1/2 trial was run in chemotherapy and hormone therapy-resistant metastatic prostate cancer patients (mCRPC). The therapeutic anti-OX40 antibody was given in three doses, on top of radiation therapy and escalating doses of cyclophosphamide. Expansion of CD4+ T cells, CD8+ T cells and NK cells was observed. This observation supports the hypothesis that OX40 agonism promotes the proliferation and survival of activated T cells, the proposed mechanism of action. In mice OX40 signaling also supports the differentiation of activated T cells into memory T cells that are required for long term protection. There is no corresponding human data yet. There was no expansion of the Treg subset (FoxP3+) except at the highest dose of cyclophosphamide. There were transient changes in circulating PSA, and 5/9 patients, metastatic lesions were stable during the course of the study. Importantly, given that we know that T cells must first be activated in order to express OX40, monotherapy may not be the best setting for testing anti-OX40 agents.
This is a promising start that gives us a few things to think about: 1) PSA was not a useful biomarker, at least in this patient cohort, although larger sample sizes may help sort this out; 2) the immune response was measured in the peripheral blood, not from TILs recovered from the tumors – be nice to see that data; 3) there were no DLTs and the therapeutic appeared safe.
Given that some of the most provocative data being generated around this pathway is in the setting of combination immunotherapy, those trials can be expected to start over the next few years. A combination trial of anti-OX40 plus ipilimumab (anti-CTLA4) in metastatic melanoma was recently withdrawn. It was to be run by the Ludwig Institute for Cancer Research, as sponsored by AgonOx. The rights to the program have gone to Medimmune/AstraZeneca and this may simply reflect a desire to proceed with a better anti-OX40 antibody (the current one being a mouse antibody). If anyone knows the back story here please share in the comments.
OX40 agonist antibodies are a hot commodity. Some recent deals involving OX40 assets are shown below:
Importantly, all of these deals involve human or humanized antibodies. This should reduce the anti-drug responses seen in the early Phase 1/2 trials that limited dosing.
No doubt there are other deals in the works. The level of activity is driven by the early clinical observations, the apparently favorable toxicity profile, and key advances in the preclinical literature. Several examples of interesting preclinical results include the data demonstrating that anti-OX40 antibody can deplete Tregs directly via engagement of Fc-receptors. The degree of depletion in this mouse model was correlated with the intensity of expression of OX40, with the highest expression found on intra-tumoral Tregs. This is an interesting finding although the translational relevance remains unclear as human Tregs only OX40 when activated through the TCR, and even then expression levels are lower than in mouse. Further, other studies have shown that anti-OX40 antibodies can activate Tregs in mouse tumor models, so there is certainly some complexity here. An attractive hypothesis is that the degree of depletion/activation of Tregs depends not only on the degree of OX40 expression but also the biophysical properties of the antibody (potency, valency, composition of the Fc-binding domain).
Also of critical interest (as mentioned above) will be the utility of anti-OX40 in combination therapies. Preclinical data suggest that OX40 agonism is synergistic with CTLA4 blockade (ipilimumab), PD-1 blockade, 4-1BB agonism, IL-2 cytokine treatment, and targeted small molecule therapeutic drugs. This is rich landscape and we anticipate an explosion of clinical data as fully human anti-OX40 antibodies begin moving through clinical trials.