Background: Despite remarkable clinical success, adoptive T-cell therapy (ACT) with anti-CD19 chimeric antigen rector (CAR) T cells is hindered by both pro-inflammatory and immuno-suppressive adverse events. Hyper-activation of CD19 CARs can trigger life-threatening cytokine release syndrome (CRS), while xenogeneic sequences in existing constructs can lead to diminished CAR T cell efficacy due to immunogenecity. Methods: To ameliorate these problems we developed a novel chimeric T-cell therapy platform, ARTEMIS, that functionally matches the potency of CAR T cells, but dramatically reduces the release of cytokines upon killing of target-positive tumors. To minimize the immunogenicity, we created a panel of fully-human CD19 antibodies using a human antibody library against cells expressing endogenous CD19. The CD19 antibodies were expressed as either ARTEMIS T cells or 2nd generation CD28z CAR T cells and tested for efficacy and safety both in vitro and in vivo. Results: In the Raji-lymphoma model with NSG mice, CD28z CART cells caused lethality within 24 hrs of T-cell injection into immunodeficient mice and led to pathologies resembling a pre-clinical CRS model. Strikingly, ARTEMIS T cells armed with the same anti-CD19 antibody showed no signs of toxicity and had potent anti-tumor effects. Both ARTEMIS and CAR T-cells engineered with our CD19 antibodies killed CD19+ cell lines with high specificity and potency. Compared to CAR, ARTEMIS T-cells have similar degranulation activity, intracellular cytokine production, and in vitro killing efficiencies. However, ARTEMIS T-cells release up to 1000-fold less cytokines and accumulate less exhaustion markers during in vitro killing assays. Conclusions: The therapeutic potential of CD19 CAR T cell therapy can be expanded with a better safety profile. The fully-human anti-CD19 antibody would reduce the risk of immunogenicity as compared with the mouse anti-CD19 antibody currently used in CAR T therapy. The ARTEMIS T-cell signaling platform was designed to be a safer ACT by relying on endogenous T-cell signaling factors. We show evidence that ARTEMIS begins to disentangle efficacy from CRS and holds the potential to be a clinically safer therapy by preventing ACT-triggered CRS.