LIGHT-ing Up Prostate Cancer for Immunotherapy
Abstract
Rationale: Although primary prostate cancer can be diagnosed early and treatment options are favorable for most patients, there are currently no curative treatments for patients with advanced or metastatic prostate cancer. One promising strategy to treat advanced disease may be cancer immunotherapy, where the patient s immune system is stimulated to recognize and attack their tumor. Provenge, the first Food and Drug Administration (FDA)-approved therapeutic vaccine for advanced prostate cancer, has been shown to increase survival but only by approximately 4 months compared to standard of care. One way to improve the effectiveness of therapeutic vaccines is to combine them with strategies that block the blood cell supply of tumors, mediate direct killing of tumor cells, and change the environment of the tumor such that T cells become more effective in eliminating tumor cells. Objective: Our long-term objective is to develop a combined tumor targeting therapy that results in cutting off the blood supply of tumors, in direct tumor cell killing, and in anti-tumor immune cell activation and that will result in tumor eradication and increased survival in prostate cancer patients with advanced disease who become resistant to standard of care treatments. Approach: Two newly made bi-specific fusion proteins, scFv-DLL4-LIGHT and scFv-EphB4-LIGHT, will be used in combination with vaccination against proteins expressed by prostate tumors as an immunotherapy approach. DLL4 and EphB4 will bind to tumor blood vessels and to the tumor cells and will guide expression of LIGHT, which is a protein that activates immune cells and allows them to function properly. These fusion proteins will be tested using preclinical models of prostate cancer. In addition, the fusion proteins will be combined with a prostate cancer vaccine to boost the immune response against proteins that are overexpressed by prostate tumor cells. Potential Clinical Application: This combination treatment with scFv-DLL4-LIGHT or scFv-EphB4-LIGHT and prostate cancer immunotherapy may bring hope to patients who have unresectable tumors that are resistant to standard therapies such as chemotherapy. The two bi-specific proteins can be easily produced for human patients once proof of concept is established in this preclinical animal model. Animal testing is required by the FDA before any therapy can be tested in humans. Recently, both DLL4 and EphB4 antibody clones have been fully humanized by us; thus, we anticipate quick translation to the clinic when positive results are obtained from the current study. Our team has experience and equipment to make clinical-grade proteins, which will also facilitate transition of our strategy to patients. Potential Risk: Prostate cancer immunotherapies should induce an autoimmune response, where normal healthy prostate tissue can be affected; however, the prostate is an expendable organ. The chance of widespread autoimmunity is minimal since expression of prostate tumor associated antigens in other tissues is very limited or nonexistent. The safety and side effects of our combination treatment approach will be evaluated in animals before being tested in humans to reduce the risk of finding negative side effects in patients. Recombinant antibody proteins are widely used in humans, and in particular antibody fragments have a short half-life; therefore, the risk of potential side effects are minimal. Estimated Timeframe to Patient-Related Outcome: Our team has expertise in designing and producing proteins for clinical trial use. When shown to be successful in our preclinical prostate cancer model, which is required by the FDA, this approach can be quickly translated for human studies. It is expect that this treatment option may reach human clinical trials within 2 years after the project is completed. Contribution to the Field: This therapeutic strategy has never been tested in prostate cancer or in any other c
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510491
Entities
People
- Wijbe Kast
Organizations
- United States Army
- University of Southern California