A. J. Olszewski, K. Aizawa, Y. H. Karimi, D. Sano, S. Y. Oh, A. Neuhof, D. Bouyoucef-Cherchalli, J. Wang, A. SyBing, M. Rodriguez, and V. T. G. Lin equally contributing author. Introduction: Although advances in adaptive, T cell-engaging immunotherapy have improved the prognosis of patients (pts) with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL), activation of innate immunity is a novel therapeutic approach. Maplirpacept is a recombinant SIRPα-blocking fusion protein designed to enhance phagocytosis and antitumor activity by disrupting inhibitory CD47-SIRPα signaling and has shown preliminary efficacy against DLBCL. This Phase 1b/2 study (NCT05626322) aimed to evaluate the safety, tolerability, and clinical benefits of the maplirpacept, tafasitamab, and lenalidomide combination in R/R DLBCL pts who are ineligible for high-dose chemotherapy (HDC) and/or autologous stem cell transplantation (ASCT). Results from the Ph1b trial are presented. Methods: Pts were aged ≥ 18 years with histologically confirmed R/R DLBCL, had ≥ 1 line of prior systemic treatment (tx; including an anti-CD20 containing regimen), and were not candidates for HDC/ASCT. Pts received maplirpacept IV 4 mg/kg, 10 mg/kg or 18 mg/kg + tafasitamab IV 12 mg/kg + lenalidomide 25 mg orally. For Ph1b, the primary objective was evaluation of dose-limiting toxicities (DLTs) during the 28-day DLT observation period; secondary objectives were safety, antitumor activity, pharmacokinetics (PK) and immunogenicity. Results: At data cut-off (December 13, 2024), 6 pts were evaluable for safety, and 5 were evaluable for DLTs. Median age was 58.5 years (range 40–81), 3 pts were male, 2 had bulky disease (longest diameter ≥ 7.5 cm), 3 had > 1 prior lymphoma-directed tx. No pts experienced DLT. Tx-emergent adverse events (TEAEs) of grade (G) ≥ 3 experienced by ≥ 2 pts were neutropenia (4 pts), thrombocytopenia, sepsis, and urinary tract infection (2 pts each). Maplirpacept tx-related AEs (TRAEs) G ≥ 3 were neutropenia (2 pts), thrombocytopenia and anemia (1 pt each). Three pts experienced serious AE (SAE); sepsis was the only SAE reported in > 1 pt. One TR-SAE (leukemia) resulted in death, unrelated to maplirpacept; a second death (cardiac arrest) occurred > 28 days after the last tx dose and was deemed unrelated to study tx. No TEAEs led to study tx discontinuation. TRAEs leading to dose interruption of maplirpacept were reported in 2 pts. Objective responses were observed in 4 pts, and all were complete responses; 1 pt had stable disease. The median duration of response was 9.6 mos; median progression free survival was 11.4 mos; median duration of tx with maplirpacept was 37 wks. Maplirpacept PK concentrations were consistent with previous datasets. No pts experienced anti-drug antibodies. Conclusions: Addition of maplirpacept to tafasitamab and lenalidomide showed clinical activity and tolerable safety profile in pts with R/R DLBCL. Although this trial was discontinued due to enrollment challenges, further development of maplirpacept for R/R DLBCL continues in NCT05896163. A genAI tool (Feb25; Pfizer; GPT-4o) developed draft 1; authors assume content responsibility. Research funding declaration: The study is sponsored by Pfizer. Medical writing support was provided by Haniya Javaid, BSc, of Engage Scientific Solutions, and funded by Pfizer. A Pfizer proprietary AI tool was used with author review to develop the first draft (February 2025); authors take full responsibility for the content. Keyword: immunotherapy Potential sources of conflict of interest: A. J. Olszewski Consultant or advisory role: Genmab, Blue Cross and Blue Shield of Rhode Island, Schrodinger, ADC Therapeutics, BeiGene, Bristol-Myers Squibb Other remuneration: Research Funding: Genentech/Roche, Precision Biosciences, Genmab, Artiva, Pfizer, Kymera Y. H. Karimi Consultant or advisory role: Yes Honoraria: Yes Other remuneration: Speakers Bureau, and Research Funding A. Neuhof Employment or leadership position: Pfizer employee Stock ownership: Yes D. Bouyoucef-Cherchalli Employment or leadership position: Pfizer employee Stock ownership: Yes J. Wang Employment or leadership position: Pfizer employee A. SyBing Employment or leadership position: Pfizer employee M. Rodriguez Employment or leadership position: Pfizer employee Stock ownership: Yes