The Promise of IL-21 Engineered NK Cells in Glioblastoma Treatment
Mayra Shanley, PhD, discussed background and future directions for evaluating IL-21 natural killer cells for the treatment of glioblastoma.
Mayra Shanley, PhD
Glioblastoma (GBM) is among the most aggressive and deadly forms of brain cancer, with current treatment options offering limited success. While standard therapies consist of surgery, radiation, and chemotherapy, they often fail to provide long-term control of the disease, leaving experts searching for more effective treatment strategies.1
One avenue being investigated is the potential of the immune system, particularly natural killer (NK) cells for combating GBM. NK cells are known for their ability to target and destroy tumor cells without prior sensitization. While they play a key role in cancer immunotherapy due to their strong antitumor activity, significant challenges for NK cell-based therapies remain.
Researchers like Mayra Shanley, PhD, sought to evaluate the effectiveness of NK cells that express either interleukin (IL)-15 or IL-21 against GBM, and found that IL-21 NK cells outperformed IL-15 NK cells in terms of safety and long-term tumor control. IL-15 NK cells were shown to be more toxic when administered directly to the tumor site.
Though early, these findings show the potential of IL-21 engineered NK cells as a promising treatment for GBM. Research will continue to evaluate IL-21 NK cells and their potential impact on GBM outcomes.
In an interview with Targeted OncologyTM, Shanley, principal research scientist at The University of Texas MD Anderson Cancer Center, discussed background and future directions for evaluating IL-21 NK cells for the treatment of GBM.
Targeted Oncology: Could you discuss the significance of using IL-21 in enhancing the antitumor activity of NK cells against GBM stem cell-like cells?
Shanley: We chose to engineer NK cells with IL-21 because we observed that cytokines have the potential to enhance NK cell cytotoxicity. Specifically, we investigated 2 cytokines, IL-21 and IL-15, to evaluate their effects. We observed that IL-21 was particularly effective in maintaining the long-term cytotoxicity of NK cells. Our previous work had shown that glioblastomas are highly susceptible to NK cell-mediated killing. However, when NK cells were exposed to increasing numbers of tumor cells, they gradually became dysfunctional. IL-21 addressed this challenge by preventing dysfunction and enabling NK cells to sustain their cytotoxicity over an extended period.
Human brain activity: © See Less - stock.adobe.com
How do IL-21 engineered NK cells compare with those engineered with IL-15?
In vitro, IL-21 and IL-15 engineered NK cells show similar efficacy in tumor killing. However, in vivo, the situation is very different. In our studies, we used mice implanted intracranially with patient-derived glioblastoma cells. Since NK cells do not effectively reach the brain after intravenous injection due the blood-brain barrier, we administered the NK cells directly into in the brain tumor. We observed that IL-21 NK cells effectively eradicated the tumor without causing toxicity, leading to prolonged survival of the mice. In contrast, mice treated with IL-15 NK cells injected directly into the brain died early due to severe toxicity. This toxicity was route-dependent; IL-15 NK cells injected intravenously showed no toxicity and have been safely used in clinical trials, as documented in our previous work.
What are the potential clinical implications of these findings for the current treatment landscape of glioblastoma?
We are currently working to translate our research findings to the clinic. Specifically, our team is developing IL-21 armored NK cells that are engineered to express a chimeric antigen receptor [CAR] targeting glioblastoma tumor antigens. Our goal is to initiate a clinical trial for this approach in 2025, addressing the urgent need for more effective treatments for this devastating disease.
What challenges do you foresee in translating these preclinical findings into clinical trials?
While our team has a proven track record of translating preclinical discoveries to the clinic, including for patients with glioblastoma, the process of securing FDA approval is ongoing and requires meticulous preparation and validation.
What are the potential benefits of using IL-21 NK cells compared with other emerging immunotherapies in the treatment of glioblastoma?
NK cells have the advantage of being off the shelf. Unlike therapies that require the engineering of cells from the patient, NK cells can be sourced from an allogenic donor such as cord blood. These cells can be administered without the need for HLA matching. This approach allows us to generate, freeze, and store our product for future use, significantly reducing production time compared to CAR T-cell therapies, which involve lengthy engineering processes and extended turnaround times.
What should your colleagues be aware of with this research moving forward?
We have shown that IL-21-engineered NK cells are both safe and effective against glioblastoma. They effectively kill tumors and sustain NK cell function in the tumor microenvironment over time. In contrast, IL-15-engineered NK cells, when administered directly into the brain can cause toxicity, which suggests that intracranial injection of IL-15 transduced NK cells should be avoided.
