Li Tang: We discovered that IL-10-expressing CAR T-cells resist T cell dysfunction and mediate durable clearance of solid tumors and metastases
Li Tang, Associate Professor at the Swiss Federal Institute of Technology Lausanne (EPFL), shared a post on LinkedIn:
“Our lab’s new paper is now out at Nature Biotechnology. We discovered that IL-10-expressing CAR T-cells resist T cell dysfunction and mediate durable clearance of solid tumors and metastases. CAR T-cells are remarkably effective in treating blood cancers, but not solid tumors. Antigen stimulation and immune suppressors cause T cell exhaustion and eventually dysfunction. Countering T-cell exhaustion is required to enhance CAR T-cell therapy for solid tumors.
We previously reported that T cells upregulate IL-10-receptor expression when they become terminally exhausted (TCF1-TIM3+). IL-10–Fc fusion protein could reinvigorate terminally exhausted T cells and induce durable complete responses in solid tumors. However, to maintain adequate concentrations, multiple intratumoral injections of IL-10–Fc were necessary limiting the application. We designed and prepared IL-10-secreting CAR T using both mouse and human CAR T-cells.
We show that treatment with IL-10-CAR T-cells leads to complete regression of established solid tumors and metastatic cancers across several cancer types in syngeneic and xenograft models, including colon cancer, breast cancer, melanoma, lymphoma, and pancreatic cancer.
The superior antitumor effects of IL-10-producing CAR T-cells challenge the conventional view that IL-10 is solely an immunosuppressive cytokine. Insights into the complex functions of cytokines could lead to further biomedical applications.
The IL-10-secreting CAR T-cell described here can potentially be a generalizable approach to prevent T cell exhaustion and metabolic dysfunction, which we term ‘metabolic armoring’. Extension to TCR-T, TIL, and other cell therapy can be expected. Clinical trials of IL-10-CD19-CAR T cells in patients with relapsed/refractory DLBCL or B-cell ALL are currently underway (NCT05715606, NCT05747157, NCT06120166). 12/12 patients have reached complete remission so far with 1-5% of typical CAR-T doses.
We are thrilled that Research Briefing has highlighted our work. Hongbo Chi, St Jude Children’s Research Hospital comments “this is an interesting study with strong therapeutic relevance”. This work was led by Yang Zhao and Jiangqing Chen, and in close collaboration with Jie Sun lab and YugangGUO2 Lab, at Zhejiang University. We also thank the Santiago Carmona lab, and Pedro Romero lab, and other Li Tang lab members, and core facilities – it was a real team effort!
We are also grateful for the support from Swiss Federal Institute of Technology Lausanne and our funding sources: Swiss National Science Foundation, Swiss Cancer League, Swiss Cancer Research Foundation, European Research Council, XtalPi, Kristian Gerhard Jebsen Foundation and Anna Fuller Fund Grant.”
Source: Li Tang/LinkedIn