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Background Chimeric antigen receptors (CAR) are synthetic receptors that combine an antigen-specific extracellular domain with key functional intracellular domains of a T cell receptor (TCR). While regulatory approval for CD19 targeting CAR-T cell therapy has been achieved for acute lymphoblastic leukemia (ALL), diffuse large B cell lymphoma (DLBCL), and primary mediastinal large B cell lymphoma (PMBCL), this therapy in other cancers which also express CD19 requires further optimization. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor engagement (signal 1), co-stimulation (signal 2), and cytokine engagement (signal 3). Current clinical CAR-T cell therapies provide signals 1 and 2, but not signal 3. The forced expression of cytokine genes in CAR-T cells improves their persistence and antitumor effects in vivo, highlighting the importance of signal 3 for CAR-T cell functions.Methods To investigate the safety of CAR-T cells incorporating signal 3, we embarked on a clinical trial ( NCT05963217) with the novel ‘JAK/STAT’ CAR.1 We developed a CD19 CAR construct capable of inducing cytokine signaling upon antigen stimulation with a JAK/STAT CAR that encodes a truncated cytoplasmic domain of IL-2Rβ and a STAT3-binding YXXQ motif together with CD3ζ and CD28 domains (28-ΔIL2RB-z (YXXQ)). A retrovirus vector encoding the novel JAK/STAT CAR was used. We embarked on a single institution, investigator initiated clinical trial with ‘in house’ manufactured CD19 JAK-STAT CAR T-cells targeting CD19+ lymphoma or chronic lymphocytic leukemia (CLL).Results To date, 4 subjects have received CART T-cell infusions. In Cohort 1, 3x10 5/kg JAK/STAT CAR-T cells were infused into 3 subjects: 2 follicular lymphoma (FL) and 1 CLL. One subject with CLL was treated in Cohort 2 (1x106/kg). In all patients, no severe adverse events were observed other than expected hematological complications. One FL patient treated with the lowest dose experienced a complete metabolic response lasting 9 months. The CLL patient treated in Cohort 2 achieved minimal residual disease (MRD) negative status which continues 9+ months. Both of these responding patients demonstrated engraftment of CAR-T cells and no dose limiting toxicities.Conclusions Next generation CAR-T cell therapy incorporating JAK/STAT signalling is safe at initial doses studied and demonstrates promising clinical activity.Trial Registration clinicaltrials.gov registration number is NCT05963217.Reference Kagoya, Y. et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nature Medicine 2018; 24: 352–359.Ethics Approval This abstract presents results from a clinical study that has obtained Research Ethics Board approval (UHN CAPCR# 22-2039) and is registered at clinicaltrials.gov (NCT05963217).