Fowler, Nathan

Abstract Varlilumab is a monoclonal antibody with agonistic activity on CD27. The efficacy of single-agent PD-1 inhibitors on aggressive B-cell non-Hodkin lymphoma is limited. Preclinical and phase 1 data suggest that Varlilumab is safe and may have synergistic activity with PD-1 inhibitors. In the DIAL study, we explored whether dual immunomodulatory therapy with Varlilumab and Nivolumab in patients with relapsed/refractory aggressive B-NHL was safe and effective. We conducted a randomized phase II clinical trial on adult patients with relapsed/refractory aggressive B-NHL. Patients were randomized to receive Nivolumab monotherapy in the control group and Varlilumab combined with Nivolumab in the experimental group. Crossover to the experimental group was allowed upon progression in the control group. The primary endpoint was the overall response rate based on the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). 54 patients underwent randomization, and 51 received assigned intervention and were included in the intention-to-treat analysis. Objective response was observed in 6 out of 51 patients (ORR 12%). There were 4 responders (ORR 16%) in the Nivolumab group and 2 responders (ORR 7.6%) in the Nivolumab and Varlilumab combination group (p = 0.3). None of the 7 patients that crossed over to the experimental group responded to the addition of Varlilumab. The ORR of patients who were previously exposed to CAR-T cell therapy was 13% (5 out of 39) compared to 8.3% (1 out of 12) in the unexposed patients (p > 0.99). The rate of treatment emergent adverse events was similar between groups, and there was no fatal TEAE in the study. The addition of Varlilumab to Nivolumb did not improve outcomes in patients with aggressive B-NHL. Even though this trial was not designed to evaluate immunotherapy as a rescue therapy after CAR-T failure, most patients (76%) had previously received CAR-T therapy, and their outcomes were equally poor.

Abstract Germinal center (GC)-derived lymphomas arise within a specialized immune ecosystem, yet whether malignant cells direct its remodeling remains unclear. Integrating genomic, transcriptomic, spatial, and functional analyses across follicular lymphoma and diffuse large B-cell lymphoma, we define a developmental framework linking malignant B-cell differentiation state to tumor microenvironment (TME) organization. Rather than segregating by histology, lymphomas align along a shared differentiation continuum in which proliferative dark zone (DZ) states associate with immune-depleted TMEs, whereas post-GC/memory B-cell (MBC) states drive inflamed but immunosuppressed TMEs. Spatial profiling reveals collapse of GC architecture and emergence of suppressive myeloid niches along this trajectory. Single-cell lineage reconstruction uncovers a DZ-to-MBC developmental axis underlying lymphoma evolution. Genetic reprogramming in vivo demonstrates that malignant differentiation state is sufficient to instruct TME remodeling. Collectively, these findings establish malignant differentiation state as a causal determinant of immune architecture across GC-derived lymphomas and identify lineage-directed immune reprogramming as a potential therapeutic strategy.

The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001 ) demonstrated improved efficacy for lenalidomide plus rituximab (R 2 ) versus rituximab with placebo (R-placebo) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Here, we present the long-term follow-up results and prespecified subgroup analyses of patients with follicular lymphoma (FL), including those 70 years and older. Patients with R/R grade 1 to 3a iNHL were randomly assigned 1:1 to receive R 2 or R-placebo. In this long-term follow-up report, progression-free survival (PFS) was assessed per the investigator. Secondary end points included overall survival (OS) and safety. Of the 358 randomly assigned patients (intent-to-treat [ITT] population), 295 had FL (≥70 years, n = 66). At long-term follow-up (median, 65.9 months), in the ITT iNHL population, PFS (hazard ratio [HR], 0.50 [95% CI, 0.38 to 0.66]) and OS (HR, 0.59 [95% CI, 0.37 to 0.95]) were improved with R 2 versus R-placebo. Safety findings were consistent with the primary analysis. Improved long-term efficacy with R 2 versus R-placebo and manageable safety with R 2 were observed in patients with FL, including those 70 years and older. With a follow-up of >5 years, data from the AUGMENT trial continue to support the use of R 2 as a standard of care for patients with R/R iNHL.