Background: The B- and T-lymphocyte attenuator (BTLA) is an inhibitory receptor expressed on B, T and NK cells. Using PBMC derived from melanoma patients, co-blockade of the BTLA and PD-1 pathways improved antigen specific T cell response compared to either blockade alone. Icatolimab (JS004 or TAB004) is a humanized IgG4 monoclonal antibody with a hinge mutation (S228P) that binds BTLA and blocks its interaction with its ligand HVEM. In this first-in-human study, we report the preliminary safety and anti-tumor activity of icatolimab as a single agent or in combination with toripalimab (anti-PD-1) in patients with relapsed /refractory (R/R) lymphoma. Methods: Eligible patients with R/R lymphoma were enrolled in this open-label, multicenter study (NCT04477772). Icatolimab was administered as a monotherapy at escalating doses of 1, 3 and 10 mg/kg intravenously Q3W and followed by 3 mg/kg and 200 mg monotherapy dose expansion until disease progression or intolerable toxicity. During combination dose escalation, patients received ascending doses of icatolimab (100mg and 200mg) plus toripalimab (240mg). Dose-limiting toxicity (DLT) was evaluated by a safety monitoring committee. Study objectives included safety, pharmacokinetics, and efficacy. Results: A total of 31 patients were enrolled, including 9 in the monotherapy dose escalation, 16 in the monotherapy dose expansion and 6 in the combination dose escalation. The lymphoma subtypes included 15 Hodgkin’s lymphoma and 16 non-Hodgkin’s lymphoma. The median age was 40 (range 21-70) years with 20 (64.5%) male patients. The median prior line of therapy was 4 with 19 (61.3%) received prior anti-PD-1/L1 therapy. By the cutoff date of January 31 2022, the median follow-up was 22.7 weeks. No DLT was observed in either monotherapy or combination dose escalation. Twenty-nine (93.5%) patients experienced treatment emergent adverse event (TEAE), with 6 (19.4%) experienced grade 3 or above TEAEs. The most common TEAEs were anemia (29.0%) and fever (22.6%). Four treatment-related adverse events led to discontinuation of the study drug. 10 (40.0%) and 6 (100%) patients experienced immune related AE in the monotherapy and combination subgroups respectively, but all were grade 1 or 2. Among 22 evaluable patients receiving monotherapy, 1 PR (follicular lymphoma) and 7 SD were observed per Lugano criteria. By the cutoff date, among 5 evaluable patients receiving the combination (all progressed upon prior anti-PD-1 therapy), 2 PR (ORR 40%) and 1 SD were observed. BTLA receptor was fully occupied in all doses evaluated. The mean half-life of icatolimab was 13.3 days. Biomarker analysis indicated HVEM positivity was associated with favorable response. Conclusions: Icatolimab alone or in combination with toripalimab were well tolerated in all doses evaluated and showed preliminary clinical efficacy in patients with R/R lymphoma. Clinical trial information: NCT04477772.