Abstract
Adoptive T cell immunotherapy has received considerable interest in the treatment of cancer. In recent years, chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising therapy in cancer treatment. In CAR T therapy, T cells from the patients are collected, reprogrammed genetically against tumor antigens, and reintroduced into the patients to trigger an immense immune response against cancer cells. CAR T therapy is successful in hematologic malignancies; however, in solid tumors, CAR T therapy faces multiple challenges, including the on-target off-tumor phenomenon, as most of the tumor-associated antigens are expressed in normal cells as well. Consequently, a transient in vitro-transcribed anti-mRNA-based CAR T cell (IVT mRNA CAR T) approach has been investigated to produce controlled cytotoxicity for a limited duration to avoid any undesirable effects in patients. In vitro and in vivo studies demonstrated the therapeutic ability of mRNA-engineered T cells in solid tumors, including melanoma, neuroblastoma and ovarian cancer; however, very few clinical trials are registered. In the present review, we discuss the effect of IVT mRNA CAR T therapy in preclinical studies related to hematologic malignancies and solid tumor management. In addition, we discuss the clinical trial studies based on IVT mRNA CAR T therapy in cancer.
Highlights
In recent years, adoptive T cell immunotherapy has emerged as a promising therapy for cancer patients
They observed that the presence of a IgG1-CH2CH3 spacer in the CD19-targeted mRNA chimeric antigen receptor (CAR) construct inhibited the cytotoxic efficacy of the reprogrammed CAR T cells in a mouse Nalm-6–Acute Lymphoblastic Leukemia (ALL) xenograft model
The authors found similar protection in a mouse model of disseminated intraperitoneal tumors obtained from a malignant mesothelioma patient after injecting mesothelin-targeting IVT mRNA CAR T cells derived from the same patient, which suggested that autologous T cells may be redirected against TAAs through IVT mRNA
Summary
Adoptive T cell immunotherapy has emerged as a promising therapy for cancer patients. In a primitive in vitro study, Rabinovich et al demonstrated the cytotoxic efficacy of human chimeric immune receptor T cells modified with mRNA which targeted B cell surface antigen CD19. This antigen is expressed in normal B cells and B cell-derived malignancies [10]. Almåsbak et al documented the possible role of the non-signaling constituents present in CAR constructs [17] They observed that the presence of a IgG1-CH2CH3 spacer in the CD19-targeted mRNA CAR construct inhibited the cytotoxic efficacy of the reprogrammed CAR T cells in a mouse Nalm-6–ALL xenograft model.
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