Background: Although CD19 directed CAR T cell therapies have improved outcomes for non-Hodgkin's lymphoma (NHL) patients, only about 30-40% of 3L+ patients obtain long term remission after this treatment (Neelapu et al. 2017; Schuster et al. 2019). bbT369, a next generation, dual targeted (CD79a/CD20), gene edited (CBLB gene knock out) autologous CAR T cell therapy was devised to overcome hypothesized mechanisms of CD19 CAR T cell treatment failure including loss/downregulation of target antigen, loss of co-stimulation pathways on tumor cells, exhaustion of CAR T cells, and CAR T cell dysfunction due to an immunosuppressive microenvironment (Shah and Fry 2019). bbT369 uses an OR gated design to limit antigen escape and contains split costimulatory domains (CD28 and 41BB) to enhance T cell activation. Methods: CRC-403 (NCT05169489) is a non-randomized, open label, multi-site phase 1/2 study enrolling relapsed and/or refractory B cell non-Hodgkin’s lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL), high-grade B cell lymphoma (HGBCL), primary mediastinal (thymic) large B cell lymphoma (PMBCL), follicular lymphoma (FL) 3b, and DLBCL transformed from FL (tFL). Patients must have relapsed after ASCT or at least 2 prior lines of therapy. Patients with tFL must be relapsed after receipt of ASCT or at least 2 prior therapies after documentation of transformation. Patients with previous exposure to non-investigational CD19 directed CAR T cell therapy who did not experience disease progression within 6 weeks of initial CAR T cell infusion are eligible for enrollment. Approximately 50 patients will be enrolled in the phase 1 portion. The primary endpoints of the phase 1 portion are determination of the MTD, determination of recommended phase 2 dose (RP2D) and safety. Secondary endpoints include overall response rate, complete response rate, time to response and time to next anti-lymphoma treatment. Exploratory endpoints include DOR, PFS, OS, CAR+ T cell expansion and correlations between clinical response and T cell phenotype or antigen expression on tumor cells. The starting dose of bbT369 will be 50x10⁶ CAR+ T cells and a BOIN design will be used for dose escalation/de-escalation decisions during the study. Upon establishment of the RP2D, the phase 2 portion will begin enrollment. Clinical trial information: NCT05169489.