Harnessing Innate Immunity to Improve Metastatic Breast Cancer Therapy
Abstract
Cyclin-dependent kinases 4 and 6 (CDK4/6) are proteins that become overactive in breast cancer cells causing cancer cells to divide uncontrollably, which results in tumor growth overtime. CDK4/6 inhibitors, such as palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio), are approved by the FDA and are routinely used in combination with hormonal therapy to stop progression of metastatic breast cancer. Specifically, breast cancer known as HR+/HER2- (hormone receptor positive/human epidermal growth factor receptor 2-negative) is treated with CDK4/6 inhibitors, which is the most common type of breast cancer. Patients generally tolerate CDK4/6 inhibitors well. CDK4/6 inhibitors put brakes on CDK4/6 proteins and this delays cancer cells from dividing. However, overtime tumors find ways to escape the effect of these drugs and stop responding. When this happens, tumors resume uncontrolled growth and dissemination to organs throughout the body. We have rationalized that combining CDK4/6 inhibitors with agents that can kill cancer cells weakened by the CDK4/6 inhibitor treatment will cause tumor shrinking and prevent relapses. We have discovered that treatment with CDK4/6 inhibitors changes breast cancer cells in a way that makes them sensitive to natural killer (NK) cells. NK cells are a type of immune cell that recognize and kill stressed cells and infected cells. NK cells can kill cancer cells and play an important role in limiting cancer spread throughout the body, a process known as cancer metastasis. We found that CDK4/6 inhibitor treatment can help NK cells to find breast cancer cells by making them secrete small proteins, called chemokines, that attract NK cells. Furthermore, we found that after treatment with CDK4/6 inhibitor breast cancer cells start sending kill me signals to NK cells by secreting NK cell-activating molecules and displaying NK cell-activating proteins on their surface. In our preliminary experiments we found that NK cells moved faster toward breast cancer cells and killed them more efficiently if breast cancer cells were treated with CDK4/6 inhibitors in comparison to the untreated cells. There is an experimental treatment currently being tested in clinical trials wherein donor NK cells are infused into cancer patients. This treatment is known as adoptive cell transfer of NK cells (NK ACT). Based on our laboratory findings, we expect that breast cancer tumors treated with CDK4/6 inhibitor will be particularly sensitive to NK ACT. This study will use a laboratory model of metastatic breast cancer to test whether infusion of NK cells will eliminate breast cancer tumors that were treated with CDK4/6 inhibitor. We will study how therapeutic NK cells find tumors and kill tumor cells and how long they maintain their activity after infusion to determine the most effective treatment schedule to be tested in future clinical studies. Safety of the patients is a concern for any new therapy. Side-effects of CDK4/6 inhibitors are manageable and include low blood cell count and diarrhea. While NK cell infusions are still experimental treatments, many clinical trials have been performed to date that demonstrated their safety for the patient. To avoid any unexpected additional toxicities from combining two therapies we propose to administer treatments sequentially, wherein NK cells are infused after the CDK4/6 inhibitor treatment cycle. Currently, Ibrance and Kisqali are prescribed in 3-week cycles separated by 1-week recovery period. Therefore, NK cell infusion can potentially be administered during the recovery periods. Furthermore, as a part of this study, we plan to carefully investigate any potential side effects in laboratory mice. Our ultimate goal is to develop new safe and effective therapy for patients with metastatic breast cancer. Based on the results of this study we will work with our clinical collaborators to design a clinical trial in patients. We have a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210019
Entities
People
- Anna E Vilgelm
Organizations
- Ohio State University
- United States Army