CAR-T therapy has achieved good results in treating hematologic malignancies, but it shows limited efficacy in solid tumors. Traditional CAR-T only targets one or two antigen epitopes. However, cancer cells are prone to loss antigens, enabling their escape from immune surveillance. Additionally, the activation intensity of traditional CAR-T is difficult to control in vivo, which poses safety hazards and limits its clinical application.
A research team led by Dr. LI Peng from the Guangzhou Institutes of Biomedicine and Health of the Chinese Academy of Sciences, Dr. XU Kailin from Xuzhou Medical University, and Dr. Jean Paul Thiery from Guangzhou Laboratory published a study titled "T lymphocytes expressing the switchable chimeric Fc receptor CD64 exhibit augmented persistence and antitumor activity" in Cell Reports online. Based on the property of CD64 to bind to antibody Fc fragments, the study designed a switchable CAR-T cell (CFR64 T) that can use antibodies to redirect tumor-associated antigens.
Both in vitro and in vivo experiments showed that CFR64 T cells exhibit better anti-exhaustion capabilities and antitumor persistence than traditional CAR-T cells. Notebly, mice treated with CFR64 T cells showed a significant increase in the proportion of memory-like T cells.
Further study revealed that CFR64 T cells form smaller immune synapses than traditional CAR-T cells, which activates T cells more gently. CFR64 T cells also demonstrate a more healthy mitochondrial status in response to antigenic stimulation.
This study highlights the importance of immune synapse morphology in the exhaustion and antitumor persistence of CAR-T cells, providing new ideas for improving the persistence of CAR-T and developing new CAR-T cells.
Fig. Schematic diagram of the principle of CFR64 T cell tumor killing (Image by GIBH)
Jean Paul Thiery, Ph.D, Principal Investigator; Guangzhou Laboratory, Guangzhou, China, 510005
Kailin Xu, Ph.D, Professor; Blood Disease Institution, Xuzhou Medical University, Xuzhou, Jiangsu, China, 221004
LI Peng, Ph.D, Principal Investigator; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 510530
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