ABSTRACT
Chimeric antigen receptor (CAR)-modified T cell therapy has achieved remarkable efficacy in treating hematological malignancies, but it confronts many challenges in treating solid tumors, such as the immunosuppressive microenvironment of the solid tumors. These factors reduce the antitumor activity of CAR-T cells in clinical trials. Therefore, we used the immunocytokine interleukin-12 (IL-12) to enhance the efficacy of CAR-T cell therapy. In this study, we engineered CAR-IL12R54 T cells that targeted mesothelin (MSLN) and secreted a single-chain IL-12 fused to a scFv fragment R54 that recognized a different epitope on mesothelin. The evaluation of the anti-tumor activity of the CAR-IL12R54 T cells alone or in combination with anti-PD-1 antibody in vitro and in vivo was followed by the exploration of the functional mechanism by which the immunocytokine IL-12 enhanced the antitumor activity. CAR-IL12R54 T cells had potency to lyse mesothelin positive tumor cells in vitro. In vivo studies demonstrated that CAR-IL12R54 T cells were effective in controlling the growth of established tumors in a xenograft mouse model with fewer side effects than CAR-T cells that secreted naked IL-12. Furthermore, combination of PD-1 blockade antibody with CAR-IL12R54 T cells elicited durable anti-tumor responses. Mechanistic studies showed that IL12R54 enhanced Interferon-γ (IFN-γ) production and dampened the activity of regulatory T cells (Tregs). IL12R54 also upregulated CXCR6 expression in the T cells through the NF-κB pathway, which facilitated T cell infiltration and persistence in the tumor tissues. In summary, the studies provide a good therapeutic option for the clinical treatment of solid tumors.
Subject(s)
Immunotherapy, Adoptive , Interleukin-12 , Mesothelin , Receptors, Chimeric Antigen , Animals , Interleukin-12/immunology , Interleukin-12/genetics , Humans , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/adverse effects , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/genetics , Cell Line, Tumor , Mice , Xenograft Model Antitumor Assays , Female , GPI-Linked Proteins/immunology , GPI-Linked Proteins/genetics , GPI-Linked Proteins/antagonists & inhibitors , Tumor Microenvironment/immunology , Neoplasms/immunology , Neoplasms/therapy , Receptors, Interleukin-12/genetics , Receptors, Interleukin-12/immunology , T-Lymphocytes/immunologyABSTRACT
OBJECTIVES: To study the epidemiological and clinical features of children with coronavirus disease 2019 (COVID-19) caused by Delta variant infection and their differences from children with ordinary COVID-19 (non-Delta variant infection). METHODS: Eleven children aged <14 years, who were diagnosed with COVID-19 caused by Delta variant infection from August to September 2021 were enrolled (variant group). Five children aged <14 years who were diagnosed with ordinary COVID-19 from February to March 2020 served as the control group. The epidemiological data, clinical features, and laboratory examination results were compared between the two groups. RESULTS: There was no significant difference in the proportion of children with clinical symptoms between the two groups (P>0.05). There were no significant differences in white blood cell count, lymphocyte count, and platelet count between the two groups (P>0.05), while the variant group had a lower neutrophil count than the control group (P<0.05). Lymphocytopenia was not observed in either group. Compared with the control group, the variant group had a higher proportion of children with an increase in creatine kinase isoenzyme (P<0.05), while there were no significant differences in the proportion of children with an increase in lactate dehydrogenase, D-Dimer, C-reactive protein or interleukin-6 between the two groups (P>0.05). Among the 9 children in the variant group, 5 tested positive for IgM antibody at week 2 after admission, and all children tested positive for IgG antibody. At week 3 after admission, the level of IgM antibody tended to decrease in 9 children, and the level of IgG antibody tended to decrease in 8 children. CONCLUSIONS: Delta variant is more infectious. COVID-19 caused by Delta variant infection may cause more serious myocardial damage than ordinary COVID-19 in children. In children infected with Delta variant, IgG antibody appears at almost the same time as IgM antibody.
