Targeted Chemoimmunotherapy of Drug-Resistant Ovarian Cancer
Abstract
FY22 OCRP Area of Emphasis: Develop novel therapeutic strategies for treatment and prevention Background: Ovarian cancer has the highest mortality rate among all gynecologic malignancies. When a normal ovarian cell turns cancerous, it freely spreads throughout the peritoneal cavity. The low rate of survival for ovarian cancer patients is mainly due to two factors: (1) the advanced stage of the disease at diagnosis, wherein the cancer cells have metastasized into the peritoneal cavity and (2) the inadequate efficacy of the available treatment options for recurrent disease. The standard of care for patients with primary ovarian cancer is cytoreductive surgery (removal of ovaries and visible tumors), followed by chemotherapy with platinum-based drugs (e.g., cisplatin) and/or paclitaxel. Although most ovarian tumors respond to standard of care at diagnosis, approximately 90% of patients after suboptimal surgery and 70% of patients after optimal surgery will experience a relapse within 18–24 months; this course for ovarian cancer follows the cancer stem cell model, which considers cancer stem-like cells with self-renewal capacity to be responsible for cancer recurrence and metastatic spread. While rapidly proliferating cancer cells are sensitive to chemo/radiation therapy, cancer stem-like cells are slow-growing, which helps them resist therapy. Therefore, to prevent relapse and provide survival benefits, it is crucial to eradicate both high-proliferating metastatic ovarian cancer cells as well as cancer stem-like cells. The objective of this research is to develop a targeted therapy that kills both rapidly proliferating ovarian cancer cells and slow-growing/dormant drug-resistant cancer stem-like cells and to demonstrate not only the eradication of metastasis, but also the inhibition of relapse. To achieve this goal, we have designed a novel approach that combines targeted chemotherapy with natural killer (NK) cell-based immunotherapy. The targeted chemotherapy is designed to not only target and kill the rapidly proliferating ovarian cancer cells without toxicity to normal cells, but also make the cancer stem-like cells visible and vulnerable to the NK cells. The NK cell-based therapy is designed to hunt for the remaining cancer stem-like cells that survived targeted chemotherapy. Our laboratory has engineered and isolated a unique adipose-derived stem cell clone that actively and rapidly migrates towards ovarian tumors making it possible to target and deliver potent cytotoxic drugs specifically to ovarian tumors eliminating potential toxicity to normal tissues. For NK cell-based immunotherapy, we will use NK92 cells which is an FDA-approved cell line and suitable for human use. Clinical trials data show that allogenic NK92 cells can be injected into patients safely without adverse effects. This is especially helpful to patients who have gone through multiple rounds of therapy and lost a significant number of their lymphocytes. If successful, the developed therapeutic protocol will be a pioneer in overcoming drug-resistance in recurrent metastatic ovarian cancer and in providing survival benefits for ovarian cancer patients who currently do not have any viable therapeutic option. Consequently, the success of this research project will have a significant impact on mortality in veterans, service women and their families, as well as in the general population.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310191
Entities
People
- Arash Hatefi
Organizations
- Rutgers University
- United States Army