Regional oncolytic poliovirus immunotherapy for breast cancer
Abstract
Which overarching challenge(s) does this research address? Conventional therapy for breast cancer often succeeds in controlling tumor growth in the medium term. However, mortality from breast cancers that return after first treatment success ("recurrent" tumors) or tumors that metastasize to different organs remains high. There is increasing evidence from clinical studies that engaging the immune system leads to lasting ("durable") control of cancer. An important benefit of immunotherapy is that it may work without much toxicity, since it does not rely on poisonous drugs or damaging radiation. This project aims to achieve an ambitious paradigmatic shift in the treatment of these cancers by harnessing the patient s own immune system to fight the tumor (immunotherapy) by using the oncolytic poliovirus PVSRIPO. Dr. Matthias Gromeier developed PVSRIPO by genetic engineering to remove poliovirus inherent disease-causing ability, thus making it safe. PVSRIPO naturally infects almost all cancer cells, because the receptor for poliovirus (used for entry) is abnormally present on most tumor cells. Once PVSRIPO is inside a tumor, it infects and kills the tumor cells. In addition, PVSRIPO triggers the body s immune system, which in turn prevents tumor recurrence. PVSRIPO has shown great promise in patients with brain tumor whose tumors have progressed despite all available standard cancer therapy. In some patients, PVSRIPO has demonstrated lasting, complete elimination of tumors. Remarkably, this effect was achieved with only minimal side effects, none of which were directly related to the virus itself. The patients experience with our strategy has been widely reported in the media including an in-depth CBS 60 Minutes report on March 29, 2015. The proposed project will build on this promising research by broadening the application to breast cancer. We will also test if the potency of the PVSRIPO virus can be increased by adding drugs (antibodies that block the inhibitory immune receptor PDL1) to stimulate the immune system. Such drugs are available and have been approved by the Food and Drug Administration for the treatment of skin cancers. What types of patients will it help and how will it help them? Our approach is for women who develop breast cancer that responds poorly to standard, currently available therapies. Preliminary studies show that our strategy can be used to fight different types of breast cancers (example, triple-negative breast cancers [TNBC] or inflammatory breast cancers) that are present in different sites (for example, locally, in the breast, or metastatic, in the brain) and this project will be aimed towards eradication of these tumors. TNBC accounts for 10%-20% of newly diagnosed breast cancers and has a poor prognosis. Women with TNBC have a 2- to 3.5-fold increased likelihood of distant recurrence and 2- to 4.5-fold increased risk of death within 5 years of diagnosis, which is in part due to the lack of available targeted therapies. Systemic treatment with standard chemotherapy is the standard of care for TNBC. However, less than 40% of patients with TNBC achieve eradication of their tumor with chemotherapy. Moreover, relevant to this study, PDL1 expression has been observed in 30% of breast cancer patients, which suggests that immunotherapies may be beneficial in women with TNBC. What are the potential clinical applications, benefits, and risks? PVSRIPO is already in clinical trials and has shown great promise against a devastating, uniformly lethal type of brain tumor. Brain tumor patients treated with PVSRIPO have seen their tumors shrink gradually, and eventually disappear. These patients have no lasting deficits, lead completely normal lives, and are not medicated. This paves the way for clinical application in patients with breast cancer. To apply this to breast cancer we need to: (1) demonstrate PVSRIPO bioactivity in human breast tissue, (2) examine PVSRIPO efficacy in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610354
Entities
People
- Smita K Nair
Organizations
- Duke University
- United States Army