A recent study published in Nature details the encouraging results from Phase 1 clinical trials of a novel immunotherapy approach targeting solid tumors expressing glypican-3 (GPC3). The research, led by investigators at Baylor College of Medicine and Texas Children’s Cancer Center, explored the use of chimeric antigen receptor (CAR) T-cells enhanced with interleukin-15 (IL-15).
Overcoming CAR T-cell Limitations in Solid Tumors
While CAR T-cell therapy has revolutionized the treatment of certain hematologic malignancies, its effectiveness against solid tumors has been limited. Preclinical studies suggested that the addition of IL-15, known for its role in T-cell survival and proliferation, could boost the performance of CAR T-cell based immunotherapies.
Trial Design and Results
The clinical trials evaluated GPC3-specific CAR T-cells co-expressing IL-15 in adults with hepatocellular carcinoma (HCC) and children with GPC3-expressing solid tumors, including HCC. Initial cohorts received GPC3-CAR T-cells alone, which were found to be safe, with peak cell expansion observed two weeks post-infusion. However, no objective anti-tumor responses were noted in these initial cohorts.
Subsequent cohorts were treated with GPC3-CAR T-cells armed with IL-15. These patients exhibited significantly increased CAR T-cell expansion, with 33% (4/12) demonstrating an objective anti-tumor response and 66% (8/12) experiencing stable disease for at least four weeks. Although patients receiving the IL-15 enhanced CAR T-cells experienced a higher incidence of cytokine release syndrome, the symptoms were effectively managed with additional medication.
Expert Commentary
"The findings are encouraging and a major step forward in enhancing the efficacy of CAR T cells for children and adults with solid tumors," said Dr. Andras Heczey, associate professor of pediatrics at Baylor and director of the Liver Tumor Program at Texas Children’s Cancer Center. "The correlative studies from this trial have provided unique insights into the evolution of tumor infiltrating CAR T cells, providing a blueprint to design the next generation of more effective, less toxic cellular immunotherapies."
Implications for Future Immunotherapies
This study highlights the potential of IL-15 to enhance CAR T-cell therapy for solid tumors. The observed increase in CAR T-cell expansion and anti-tumor responses suggests that arming CAR T-cells with IL-15 can overcome some of the limitations that have hindered their effectiveness in solid cancers. Further research is needed to optimize this approach and develop even more effective and less toxic cellular immunotherapies.
