Production of a Novel OX40 Ligand for Clinical Use

Cancer cells have evolved to evade immune-mediated destruction through several documented mechanisms. Our group has developed a technique to enhance immune function in tumor-bearing hosts by targeting a protein on the surface of white blood cells, termed OX40. This type of immune modulation leads to therapeutic benefit in tumor-bearing mice. We have produced a protein that binds to the human OX40 protein and activates human white blood cells. We have a cell line that produces high quantities of this protein and our goal is to test this protein for safety and efficacy in non-human primates so that we can obtain FDA (Food and Drug Administration) approval for clinical trials in cancer patients. The long-range goal of this proposal is to translate these findings to prostate cancer patients. We have just finished a clinical trial with a similar antibody that is a mouse protein and hence the patients treated mount an immune response against the mouse portion of this protein. Therefore, it can only be administered once. In the initial Phase I trial where we only treated patients with widespread metastatic disease, 7/30 patients showed partial tumor regression and another 6 had stable disease during the observation period. The protein described in this application is fully human and therefore could be administered several times without immune-mediated clearance. We believe that multiple infusions of the protein over time will have a greater impact on therapeutic outcome of patients that receive this OX40-mediated therapy. In the Phase I study with the murine anti-human OX40 Ab, we observed little toxicity at all three doses, although we have observed immune stimulatory effects. Five patients had a full body rash 3 days after OX40 Ab treatment that was resolved using anti-inflammatory drugs. Therefore, we suspect that the humanized protein will be relatively safe; however, we will learn more in the months ahead when performing monkey toxicity studies.

The funds provided from this 3-year proposal will allow us to produce clinical grade material. Once the clinical grade protein is produced, we will apply to the FDA for approval of a Phase I/II clinical trial targeted to prostate cancer patients. Our hope is to get this protein into patients within 3 years of approved funding. Our group has a proven track record of translating findings from the lab bench to patients, and we are dedicated to obtaining the results that will rapidly move our work from the 'bench to the bedside.'