RESUMO
Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks. Cohort 2 patients (NCT05103631/NCT04377932) received GPC3-CAR T cells that co-expressed IL15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared to non-responders, tumor-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members as well as genes related to type I interferon signaling. Collectively, these results demonstrate that IL15 increases the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients.
RESUMO
The American Cancer Society recently reported a second consecutive year of very positive data regarding cancer survival. Although the latest data may have been affected by pandemic-associated delays, the trend in the data indicates that the overall death rate from cancer in the United States continues to decline. The death rate from cancer has fallen 31% from 1991 to 2018, with an estimated 2.9 million fewer cancer deaths during that interval than would have occurred if death rates had remained at their peak level (based on five-year age-specific, sex-specific, and population-based data). Multiple factors have contributed to this improvement in cancer survival. For example, notable improvements in treatments for childhood cancers have resulted in overall survival increasing from 30% in the 1960s to greater than 80% in most high-income countries in 2020. In addition, vaccines against human papillomavirus are reducing cervical cancer risk, enhancement in breast cancer diagnosis and treatment have led to marked survival gains, and targeted therapies (e.g., immune checkpoint inhibitors) for malignant melanoma have increased long-term survival by 50% in some cases. However, other cancer types, such as pancreatic and brain, have seen lower levels of improvement.