Stimulation of Dendritic Cell Recruitment and Differentiation to Improve the Treatment of Metastatic Breast Cancer
Abstract
Our Breakthrough Award proposal addresses the Overarching Challenge “Eliminate the mortality associated with metastatic breast cancer.” The efficacy of metastatic breast cancer treatment is impaired in part by (1) a poor response of the immune system and (2) the poor access/delivery of drugs to cancer cells. The human immune system is composed of inhibitory cells – immunosuppressive cells – and effector cells – lymphocytes – which can kill cancer cells. The killing activity of lymphocytes is helped by dendritic cells, which produce factors that increase the abundance and killing activity of lymphocytes in tumors. Similar to lymphocytes, there is often in metastatic breast cancer lesions an insufficient number of dendritic cells, which often explains the poor activity of the immune system at combatting cancer. One major objective of our proposed study is to develop a novel oncolytic virus that will carry/express genes that will increase the abundance of dendritic cells in metastatic breast cancer lesions. Oncolytic virus can be engineered to carry/express specific genes. For example, Talimogene Laherparepvec – a genetically modified oncolytic virus that expresses a gene that leads to the activation of immune cells – was approved for the treatment of patients with metastatic melanoma in 2015. As mentioned before, another limitation of cancer treatment is the poor accumulation of therapeutic agents in tumors. Currently for the treatment of patients with cancer, oncolytic virus is generally administered directly in tumor lesions. However, intratumoral injection is technically challenging and limits the application to accessible tumor sites or localized disease. In contrast to intratumoral injections, the intravenous delivery facilitates the administration of virus and also permits the treatment of metastasis. Recent preclinical as well as clinical studies have shown the benefits of the intravenous delivery of virus for cancer treatment. However, the intravenous delivery and therapeutic efficacy of oncolytic virus is limited by vascular and other tissue barriers in tumors. We recently discovered in models of primary breast cancer that the cancer drug ganetespib breaks down the vascular barrier and improves the intravenous delivery and efficacy of oncolytic virus. Thus, in our proposed studies we will determine whether ganetespib will increase the delivery of novel oncolytic virus expressing genes that will stimulate the intratumoral access of dendritic cells and lymphocytes, and antitumor efficacy in mouse models of metastatic breast cancer. Based on our preclinical results, our tightly integrated and multidisciplinary team of investigators anticipate that successful completion of these studies will positively impact the development of new treatments for metastatic breast cancer patients who currently have a 5-year survival rate of ~26%. If our proposed approach is successful, ganetespib could be repurposed as an agent for enhancing the intravenous delivery and effectiveness of oncolytic virus in patients with metastatic breast cancer. Because ganetespib has already been tested in patients with cancer and found to be safe, the combination of ganetespib and oncolytic virus could be first tested in a clinical trial for patients with metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010017
Entities
People
- E. Antonio Chiocca
Organizations
- United States Army