While thermal ablation currently provides excellent outcomes for early-stage hepatocellular carcinoma (HCC), a new study indicates that applying nonlethal hyperthermia may also improve natural killer (NK) cell cytotoxicity and effect better outcomes for multiple HCC cell lines.
The impact of NK cell therapy on HCC cell lines—including histopathologically well-differentiated and poorly differentiated—has been recorded in a previously published paper.
The newest study, “Natural Killer Cell-based Immunotherapy Maintains Cytotoxicity after Temperature-Controlled Ablation in Poorly and Well-differentiated Hepatocellular Carcinoma,” focused on recreating the postablation tumor environment to investigate the impact of nonlethal hyperthermia on these two HCC cell lines. According to lead author Po-Chun Chen, DVM, the idea was born of a collaboration with Jason Chiang, MD, PhD, an interventional radiologist, and Anahid Jewett, PhD, an immunology professor, at the University of California Los Angeles.
“Dr. Chiang suggested treating HCC using our supercharged NK cells, which are excellent at killing solid tumors and producing interferon gamma cytokine,” said Dr. Chen. “This led to our collaboration where we began to investigate how various HCC types respond to NK cells, particularly after ablation.”
Image-guided thermal ablation is considered the standard of care for patients with nonresectable early-stage HCC. According to researchers, the peripheral zone of the ablation exposes tumor cells to nonlethal hyperthermic temperatures. Local tumor progression often occurs in these areas of nonlethal hyperthermia, presenting an unmet need for adjuvant strategies. NK cell-based immunotherapy can potentially pick off those residual tumor cells after ablation.
To determine the efficacy of NK cell-based immunotherapy after sublethal ablation, the poorly and well-differentiated HCC cell lines were incubated in hot water baths at hyperthermic temperatures (37°C, 43°C and 47°C), cooled at 25°C and then exposed to NK cells. The NK effector cells included primary NK cells, IL-2 stimulated NK cells and supercharged NK cells.
The IL-2 stimulated and supercharged NK cell therapies demonstrated increased cytotoxicity with higher cytolysis after HCC cells were incubated at 47°C compared to 37°C.
“Our research indicates that the IL-2 stimulated and supercharged NK cells become more effective at killing cancer cells when the HCC is exposed to nonlethal hyperthermia,” said Dr. Chen. “Although we know the thermal ablation works well for early-stage HCC already, recurrence can still occur. That’s why I believe our findings suggest that combining thermal ablation with adjuvant NK cell therapy could further improve the treatment outcomes.”
Dr. Chen added that her team found that the poorly differentiated HCC cells grow faster and are more resistant to hyperthermia. “This study also highlights the fact that we should consider doing biopsy for LI-RADS 5 HCC so we can use tissue biomarkers to drive clinical decisions,” she said.
Eventually, Dr. Chen said, researchers hope to devise catheter-directed methods to deliver their own supercharged NK cells to target tumors. This is an area of ongoing research in Dr. Chiang’s lab, where they are building a large animal liver cancer model in pigs, which can accommodate clinically relevant catheters and wires. In the near term, however, the next step will be translating this work into in vivo mouse models to validate the concept of combining ablation with NK cell therapy.
“Once we have our mice and pig models built out, I think the results will be promising,” Dr. Chen said. “Eventually, I think combining thermal ablation with adjuvant immunotherapy will take interventional oncology to the next level.”
