01
Previous studies have shown that CAR T cells have limited efficacy in patients with solid tumors, in part due to inhibitory signals that block immune responses and lack of supportive factors in the tumor microenvironment (TME). IL-15, which belongs to the common γ-chain cytokine family, is crucial for CD8+T cell memory formation, mitochondrial metabolism and the expansion and persistence of antigen-experienced T cells. Glypican-3 (GPC3) is specifically expressed in various solid tumor types and is absent from non-malignant tissues. In previous study, the authors showed that IL-15 co-expression improved the expansion and antitumor activity of GPC3 CAR T cells in non-clinical solid tumor models. However, the antitumor activity and safety of CAR T cells co-expressing IL-15 in human are unclear.
In this clinical study, the authors evaluated the effects of GPC3 CAR T cells co-expressing IL-15 (15.CAR) in human. They revealed that GPC3 CAR T cells were safe but produced no objective antitumor responses and reached peak expansion at 2 weeks in cohort 1 patients. Meanwhile, they demonstrated that 15.CAR mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33% cohort 2 patients. Furthermore, they found that infusion of 15.CAR T cells was related to increased incidence of cytokine release syndrome (CRS), which was controlled with IL-1/IL-6 blockade or rapidly ameliorated by activation of the inducible caspase 9 safety switch. Moreover, they showed that tumor-infiltrating 15.CAR T cells from responders displayed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members, as well as of genes related to type I interferon signaling, compared to those from non-responders. Collectively, this study reported the safety characteristics and antitumor response rates of 15.CAR T cells in patients.
DOI: 10.1038/s41586-024-08261-8
02
Multiple sclerosis (MS) is an autoimmune disease with the immune system attacking myelin sheaths, resulting in neuronal death. In this study, the authors constructed a CAR targeting myelin oligodendrocyte glycoprotein (MOG), which is expressed on the outer membrane of the myelin sheath, the insulating layer that forms around nerves. They demonstrated that human and mouse MOG-CAR Tregs displayed high signal-to-noise ratio and could be specifically activated by MOG antigen in vitro. Meanwhile, they revealed that human MOG-CAR Tregs mediated MOG-specific immunosuppression and immunomodulation in vitro. Subsequently, they showed that naive Tregs isolated from remitting-relapsing MS (RRMS) patients could be engineered to generate MOG-CAR Tregs and these Tregs were functionally active in vitro. Furthermore, they demonstrated that mouse MOG-CAR Tregs could specifically migrate to the central nervous system (CNS) of EAE mice upon inflammation. Importantly, they showed that MOG-CAR Tregs delayed the onset of EAE and reduced the activity of pathogenic cells in the CNS. Collectively, MOG-CAR Tregs developed in this study may represent a promising therapy for MS patients.
DOI: 10.1186/s12974-024-03262-w
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Editor & Reviewer: Yanwen Zhu
