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Background: Autologous T cells engineered to express a universal ACTR chimeric receptor kill tumors through interactions with tumor-targeting antibodies [Kudo, Cancer Res 2014]. ACTR707 was identified through rigorous preclinical screening of more than 100 different ACTR variants. It is composed of the extracellular domain of CD16, the cytoplasmic signaling domain of CD3ζ, and the costimulatory domain of CD28. Study ATTCK-20-03 (NCT03189836) is the first clinical trial of ACTR707. ACTR707 in combination with rituximab is being studied in subjects with relapsed or refractory CD20+ B-cell lymphoma previously treated with anti-CD20 monoclonal antibody (mAb) therapy. Herein we report data from the first dose level of ACTR707, where 6 subjects have been enrolled and treated.Methods: ATTCK-20-03 is a first-in-human, multicenter phase 1 dose escalation study of ACTR707 in combination with rituximab. The primary objective is to evaluate the safety of ACTR707 in combination with rituximab, and secondary objectives include evaluation of antitumor activity, assessment of T-cell expansion and persistence, cytokine levels, and rituximab pharmacokinetics. Eligible subjects must have histologically confirmed relapsed or refractory aggressive CD20+ B-cell lymphoma of DLBCL, MCL, PMBCL, Gr3b FL, or transformed FL subtype and have received prior anti-CD20 mAb therapy in combination with chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2 and fludarabine 30 mg/m2) for 3 days, followed by rituximab (375 mg/m2) and a single infusion of ACTR707. Additional doses of rituximab are administered, one dose every 3 weeks in the absence of disease progression. The study is separated into two sequential phases, a dose escalation and a safety expansion phase. During dose escalation, ACTR707 will be tested at increasing doses in combination with rituximab. Results: Six subjects received ACTR707 in combination with rituximab at the first dose level: 5 diagnosed with DLBCL (83%) and 1 with Gr3b FL (17%). Median age was 61 years (range: 57-76), 83% were male, 50% were treated with ≥ 3 lines of prior therapy, and 67% had no response to or progression within 6 months of immediate prior therapy. ACTR707 was successfully manufactured for all subjects. ACTR+ T cells demonstrated expansion and were detectable at D28 post-ACTR707 infusion for all subjects tested. There were no dose-limiting toxicities observed in the 4 subjects evaluable for DLTs (2 subjects were not DLT-evaluable due to early disease progression). There were no serious adverse events of cytokine release syndrome, neurotoxicity, or autoimmune events and no deaths on study. Grade 3 or higher AEs included neutropenia (n=2), febrile neutropenia (n=2), and thrombocytopenia (n=1). Antitumor activity was assessed in all 6 subjects. Three subjects experienced disease progression and 3 subjects demonstrated investigator-reported complete responses at the first disease response assessment (D42). Responses are ongoing at the time of the data cut-off. Conclusions: In the first dose level studied in subjects with relapsed or refractory aggressive CD20+ B-cell lymphoma, ACTR707 in combination with rituximab induced complete responses in 3 out of 6 treated subjects, with no serious events of cytokine release syndrome or neurotoxicity. ACTR+ T-cells were detectable in all subjects and ACTR+ T-cells persisted in the presence of continued rituximab administration. These results support the continued dose escalation of ACTR707 in combination with rituximab. Citation Format: Veronika Bachanova, Jonathon Cohen, Luke Akard, Samantha Jaglowski, Jessica Sachs, Ann Ranger, Patricia Harris, Kathleen McGinness, Greg Motz, Ian Flinn. Safety and preliminary efficacy of ACTR707, autologous T lymphocytes expressing an antibody-coupled T-cell receptor, in combination with rituximab in subjects with relapsed or refractory CD20-positive B-cell lymphoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A003.