Manipulating the Ovarian Cancer Tumor Microenvironment to Enhance Natural Killer (NK) Cell Killing
Abstract
Rationale: Ovarian cancer is the most lethal gynecologic malignancy. The majority of women with ovarian cancer present with Stage III or IV disease, for which the rate of recurrence is 60-70%. Most women will recur within 2 years of diagnosis and once they recur, they cannot be cured with current therapies. Therefore, there is an urgent need for new therapeutic strategies. Immune-based treatments have revolutionized the treatment of many cancers. Currently, there are no approved immune-based therapies for ovarian cancer, and clinical trials of immune-based therapies have shown only modest response rates. In order to exploit immune-based strategies for long-lasting, durable cure in ovarian cancer, the immune suppressive networks within the ovarian tumor microenvironment (TME) must be considered. Effective ways to exploit the body’s own immune system and to inhibit the immunosuppressive mechanisms prevalent in the TME must be developed before immune-based therapy for ovarian cancer will succeed. Our long-term research objective is to exploit the body’s own immune system to treat ovarian cancer and improve survival rates. The central problem addressed in this proposal is prevention of ovarian cancer tumor escape from the immune system and development of strategies to rescue natural killer (NK) cell function in ovarian cancer that will translate to improved outcomes. Specifically, we plan to target NK cells, a type of white blood cell, which are involved in tumor surveillance. We know that NK cells from women with ovarian cancer do not kill as well as those from healthy individuals, that women with ovarian cancer have fewer NK cells within their abdominal cavity, and that higher numbers of NK cells correlate with longer survival. Our studies will explore how to increase the number of NK cells in women with ovarian cancer and make the NK cells more efficient killers to prevent recurrence of this disease. To better understand how to increase numbers of NK cells, we will utilize ovarian cancer patient samples to evaluate the impact of the TME on NK cell function and to determine the best time to use immune-based therapies. We have been using a drug called ALT-803 (an IL-15 superagonist complex) that potently induces NK cell numbers and improves their ability to kill cancer in a clinical trial for women with advanced-stage ovarian cancer. IL-15 is a cytokine and growth factor produced naturally by the body that is capable of expanding immune cells. ALT-803 has been altered to increase the biological activity of IL-15. We recently discovered that treatment of NK cells with ALT-803/IL-15 induces expression of PD-1 (programmed cell death-1) on NK cells. PD-1 is a checkpoint present on NK cells that acts as an “off switch” to prevent immune cells from attacking healthy cells within the body. The healthy cells of the body have a receptor called PD-L1 (programmed cell death ligand-1) that, when the NK cells see this, they recognize it and do not attack. We know that by increasing expression of the PD-L1 receptor on their surface, ovarian cancer cells trick the body into thinking they are “normal cells, ” so the immune cells do not attack the ovarian cancer cells and, thereby, the cancer evades immune attack. We will create a novel Tri-specific Killer Engager (TriKE) molecule that will have a triple mission: (1) block PD-L1 on ovarian tumors; (2) target NK cells directly to the ovarian tumor; and (3) use an IL-15 linker to drive NK cell survival, activity, and expansion. We predict treatment with the TriKE will allow NK cells to overcome the immunosuppressive environment in ovarian cancer by preventing ovarian cancer cells from “hiding” from the immune system while increasing NK cell activity and tumor killing. We hypothesize that the combination of enhancing NK cell expansion and blocking of the PD-1/PD-L1 pathways with a TriKE will enhance NK cell mediated killing of ovarian cancer. Successful proof of concept
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010341
Entities
People
- Melissa Geller
Organizations
- United States Army
- University of Minnesota