Glioblastoma (GBM), a highly aggressive brain cancer, faces challenges with current treatments. Researchers are exploring natural killer (NK) cells as a potential immunotherapy, focusing on enhancing their antitumor activity through cytokine engineering. Mayra Shanley, PhD, and her team at The University of Texas MD Anderson Cancer Center, have found that NK cells engineered with interleukin (IL)-21 show promise in treating GBM, outperforming IL-15 engineered NK cells in safety and long-term tumor control.
IL-21 Enhances NK Cell Cytotoxicity
Shanley's research highlights the significance of IL-21 in maintaining the long-term cytotoxicity of NK cells against GBM stem cell-like cells. "We observed that IL-21 was particularly effective in maintaining the long-term cytotoxicity of NK cells," Shanley explained. Previous work indicated that glioblastomas are susceptible to NK cell-mediated killing, but NK cells tend to become dysfunctional when exposed to increasing numbers of tumor cells. IL-21 addresses this by preventing dysfunction and enabling NK cells to sustain their cytotoxicity over an extended period.
Safety and Efficacy Comparison: IL-21 vs. IL-15
While in vitro studies showed similar tumor-killing efficacy between IL-21 and IL-15 engineered NK cells, in vivo results revealed a critical difference. In studies involving mice implanted intracranially with patient-derived glioblastoma cells, IL-21 NK cells effectively eradicated the tumor without causing toxicity, leading to prolonged survival. In contrast, mice treated with IL-15 NK cells injected directly into the brain experienced early death due to severe toxicity. Shanley noted that this toxicity was route-dependent, as intravenous injection of IL-15 NK cells showed no toxicity and has been safely used in clinical trials.
Clinical Translation and Future Directions
The research team is actively working to translate these findings into clinical applications. They are developing IL-21 armored NK cells engineered to express a chimeric antigen receptor (CAR) targeting glioblastoma tumor antigens. The goal is to initiate a clinical trial for this approach in 2025. Shanley acknowledges the challenges in securing FDA approval but remains optimistic, given their track record of translating preclinical discoveries to the clinic.
Advantages of IL-21 NK Cells Over Other Immunotherapies
NK cells offer a significant advantage over other immunotherapies like CAR T-cells because they can be sourced from allogenic donors, such as cord blood, and administered without HLA matching. This "off-the-shelf" approach allows for faster production times compared to CAR T-cell therapies, which require lengthy engineering processes and extended turnaround times.
Key Takeaways
Shanley emphasizes that IL-21-engineered NK cells are both safe and effective against glioblastoma, effectively killing tumors and sustaining NK cell function in the tumor microenvironment over time. She cautions against intracranial injection of IL-15 transduced NK cells due to potential toxicity.
