Mechanisms and Predictors of Adoptive Cytokine-Induced Memorylike NK Cell Therapy in Renal Cell Carcinoma
Abstract
Despite recent advances in treatment, metastatic clear cell kidney cancer (ccRCC) remains fatal for most patients. Natural killer (NK) cells are an important part of the body s natural immune defenses against cancer. Prior experiments have shown that among patients with clear cell kidney cancer, decreasing NK cell function is linked with kidney cancer progression and metastasis. Restoring the function of NK cells might be a promising treatment strategy. In prior work, we have shown that NK cells taken from patients can be treated in the lab with cytokine proteins, which causes them to change into cytokine induced memory-like NK (CIML-NK) cells. These CIML-NK cells have improved survival, improved ability to grow and persist, and improved ability to kill cancer cells. We have previously shown that CIML-NK cells can lead to tumor regression in patients with myeloid leukemia and head and neck cancer. We are conducting a clinical trial to treat patients with ccRCC with CIML-NK cells. Using samples from these patients, the goal of this project is to understand how CIML-NK cell treatment works in patients. This will then help us improve the treatment for future patients. In our first aim, we will perform a deep analysis and comparison of NK cells collected prior to treatment, after cytokine treatment (to generate CIML-NK cells), and then collected from the patient after treatment. We will assess whether the treatment caused the NK cells to survive longer and whether there are changes in the NK cells protein and gene expression. We will test these NK cells, collected at different time points, in the lab to see whether our treatment strategy improves the NK cells ability to kill cancer cells. We will also analyze biopsies taken from patients to understand what effects the treatment is having on tumor cells and the tumor environment in the actual patient. Overall, this first aim will help us ensure that the CIML-NK treatment protocol is having the intended effects on patients and give us a better understanding of how these cells work in patients with ccRCC. In our second aim, we will look for signals that can indicate successful treatment, and examine potential reasons why treatment may or may not work for individual patients. This will be done by comparing various measurements (amount of NK cells collected and infused, changes in cytokine protein levels in the blood, changes in levels of other immune cells in the blood and tumor environment, changes in circulating tumor genetic material) and seeing if these are associated with the response to treatment. In patients who do not have a good response to treatment, we will check if the tumor is causing changes that cause the CIML-NK cells to be evaded or inactivated. Overall, this second aim will help us to personalize treatment to individual patients and potentially anticipate and overcome cancer resistance to treatment. The goal of the project as a whole is to help create a new treatment option for patients with clear cell kidney cancer. If successful, this will help patients to live longer and have fewer symptoms from their cancer. Since this is a new type of treatment, we seek to understand in a detailed way how the body responds to treatment, what effect the treatment has on tumors, and what factors might be associated with patients whose cancers respond versus do not respond. This research could directly benefit patients depending on the results of our clinical trial. If many responses to treatment are seen, we could move forward into larger clinical trials in the next 1 to 2 years. If few responses are seen, this project would allow us to make adjustments to future protocols that can better choose which patients are most likely to benefit from this treatment. We would also better understand how to make changes to the protocol to overcome resistance to treatment. While the focus of our study will be on CIML-NK cell treatment, this will also impr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310477
Entities
People
- Toni K Choueiri
Organizations
- Dana–Farber Cancer Institute
- United States Army