A Fusion Protein Bispecific Phagocyte Engager (BiPE) for Targeted Breast Cancer Immunotherapy
Abstract
Breast cancer is the most common cancer and a major health concern among women. Approximately 250,000 new breast cancer diagnoses are made each year, and in 10% of these patients, the cancer cells have metastasized to distant organs (stage IV). Unlike patients diagnosed with early-stage breast cancer, metastatic breast cancer carries a dismal prognosis, with a 5-year relative survival rate of only 20%. Metastatic breast cancer is also more likely to be resistant to treatment. Even with the use of new, targeted therapies such as antibodies against the human epidermal receptor 2 (HER2) expressed by cancer cells, over 70% of patients with metastatic diseases eventually become resistant to treatments. Furthermore, targeted therapy options are limited for triple-negative breast cancer (TNBC) that lacks the hormone and HER2 receptors. Unfortunately, TNBC is often more aggressive and carries a worse prognosis. Therefore, identifying new and effective treatments for highly aggressive metastatic breast cancers is an urgent and yet unmet need. The recent success of cancer immunotherapy for treatment-refractory metastatic melanoma, non-small cell lung cancers, and renal cell carcinoma has provided new hope for breast cancer patients. By harnessing the power of the body’s immune system, we can potentially eradicate some of the most highly aggressive and difficult-to-treat cancers. Applying this principle, our group recently found a strategy to educate the body’s innate immune system to recognize breast cancers by targeting specific receptors expressed by tumor and immune cells as a way to stimulate immune-mediated tumor eradication. Our current proposal aims to translate this novel treatment strategy into a new class of cancer immunotherapeutic by developing an all-protein Bispecific Phagocyte Engager (BiPE) system. The BiPE platform contains a tumor-targeting domain, which is connected to a molecule that recruits immune cells. This way, BiPE helps to facilitate immune cells to engage with cancer cells, resulting in efficient clearance of tumor cells by the body’s immune system. In addition, the BiPE technology was specifically engineered for rapid clinical translation by using an all-protein design. As a result, BiPE serves as a platform for which multiple therapeutic variants can be generated to treat different types of breast cancer in a plug-in-play fashion. Therefore, we hypothesize that BiPE systems designed to specifically target the HER2 or folate receptors (FR) would provide a new and effective immunotherapy strategy to treat HER2+ or FR+ TN breast cancers, respectively. Our current study will test this overall hypothesis by using the following specific aims. In Aim 1, we will determine if and how BiPE that are designed to target HER2 receptor (BiPE-HER2) can help the immune cells to recognize HER2+ breast cancer cells. We will also evaluate the extent of responses from the immune cells once they have recognized and engaged the cancer cells, as well as the antitumor effect generated by BiPE-HER2 against metastatic HER2+ breast cancers. In Aim 2, we will evaluate if BiPE-HER2 can enhance the efficacy of existing cancer immunotherapies such as anti-PD1 antibody against HER2+ breast cancer. The rationale behind here is that BiPE-HER2 and anti-PD1 work on different processes involved in generating antitumor immune responses. Therefore, we hypothesize that the combination treatment should produce a synergistic effect. Finally, in Aim 3, we will test the versatility of the BiPE platform and evaluate if the BiPE variant that targets the FR (BiPE-FR) can produce antitumor effect against TNBC. The clinical efficacy of immunotherapy has already been demonstrated in multiple solid tumors, with patients previously diagnosed with what were once considered “terminal” cancers now achieving long-term remission. Our proposed research will advance the field and provide new ways to boost the efficacy of immunotherapie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910325
Entities
People
- Betty Kim
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army