<p>T cell-mediated cancer immunotherapies, including chimeric antigen receptor (CAR) T cell-therapy and bispecific antibody that recruits cytotoxic T lymphocyte (CTL) to cancer cells, directly recognize surface antigens of cancer cells regardless of MHC restriction. Despite the remarkable efficacy against tumor malignancies in clinical, the CAR T cell-therapy is frequently accompanied with severe cytokine release syndrome (CRS), which is one of the draw backs of CAR T cell-immunotherapy. In preclinical study, the efficacy and safety of CAR T cell-therapy were used to be evaluated using the tumor bearing NOG models. We previously reported activation of infused CAR T cells and regression of tumor burden in tumor bearing NOG mice, in which the human cytokine release in serum was subtle. It is considered that a variety of human immune cells contribute to the CRS, so we evaluated the CRS in the NOG-EXL mice with human hematopoietic stem cell (HSC) transplantation and tumor engraftment. In the humanized NOG-EXL model, we found expansions of human T, B and myeloid cells, as well as human cytokine levels comparable to that in clinical, in mouse peripheral blood. We conclude that the humanized NOG-EXL mice with a variety of human immune cells are superior to the models currently used for projecting the propensity of CRS in the preclinical study of CAR T-immunotherapy.</p>