Combining Nanotechnology and Radiation to Enhance Checkpoint Blockade Immunotherapy of Advanced Prostate Cancer
Abstract
In 2017, approximately 166,000 men are expected to be diagnosed with prostate cancer, with the majority of cases occurring in men aged 65 and over. One in seven men will be diagnosed with prostate cancer in his lifetime. Patients are treated with surgery, radiotherapy, chemotherapy, and/or hormone therapy, depending on how advanced the disease is at the time of diagnosis. High doses of x-ray are often given after surgery to ensure they remain disease-free, which results in overtreating ~50% of these patients. Hormone therapy is often effective in reducing prostate and disseminated (metastatic) tumors or preventing tumor growth, but often fails after some time, termed recurrence, after which hormone therapy is used to lessen disease for pain management. At this point, other therapies are not always effective, but cause significant toxicities. Patients with disease that has reoccurred in the prostate and/or spread to other areas of the body will specifically benefit from improved therapy with less toxicity. Therefore, there is a pressing need for the development of new treatments that can treat both prostate and metastatic lesions. Radiotherapy has the greatest toxic and anticancer effects on the area that is directly irradiated with x-rays. This can also cause activation of the host immune system, which is designed to attack foreign species in the body, such as cancer cells. This immune response can lead to therapeutic effects against cancer cells or tumors that are disseminated in the body, but not directly irradiated. Unfortunately, the radiotherapy-activated immune response is rarely sufficient to eliminate these metastatic lesions in human patients or tested animal models. Prostate tumors are known to generally be unresponsive to treatment by a single immune stimulating agent (immunotherapy), with mixed results of currently evaluated CTLA-4 and/or PD-1/PD-L1 antibodies. There have been individual cases of immunotherapy causing significant antitumor response, but no statistically significant improvement was seen in a small clinical study. Adding radiotherapy to immunotherapy also did not significantly improve survival to patients with recurrent disease. Consequently, strategies to enhance the anticancer effects of immunotherapy in prostate cancer patients would be of great clinical interest. The Lin group has pioneered the development of a nanomedicine platform, termed nanoscale metal-organic frameworks (nMOFs), for biomedical applications. Together with Drs. Weichselbaum and Spiotto, we have recently discovered that non-toxic nMOFs enable significant x-ray-induced anticancer efficacy in a process called radiotherapy-radiodynamic therapy (RT-RDT). This efficacy has been demonstrated in multiple mouse models, including tumors representative of PCa insensitive to normal hormone therapies. The objective of this proposal is to establish RT-RDT and immunotherapy as a new treatment paradigm to address the challenges of treating recurrent and advanced PCa with low-dose x-ray irradiation. In the proposed project, we will evaluate the effects of RT-RDT on prostate cancer models via the following aspects: 1. Can RT-RDT sensitize resistant prostate cancer to radiation? We will evaluate whether RT is more effective on human prostate cancer cells and tumors from patients with advanced or metastatic disease after treatment with non-toxic nMOFs and low doses of x-ray irradiation. The underlying mechanisms of anticancer efficacy and radiosensitization will also be investigated. 2. Can RT-RDT be effectively combined with immunotherapy to control disseminated disease? Small molecule drugs will be loaded into the nMOFs to combine RT-RDT with immunotherapy in mouse models. Mice will be implanted with two tumors to investigate whether nMOF injection and irradiation of one tumor can influence the growth pattern of the other. 3. Does this technology have clinical potential in advanced models of PCa?
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810415
Entities
People
- Wenbin Lin
Organizations
- United States Army
- University of Chicago