Mosunetuzumab is highly effective against many B-cell lymphomas, but longitudinal immune changes induced by intermittently dosed CD20×CD3 bispecific antibodies remain incompletely characterized. We performed immune profiling of peripheral blood samples from patients receiving fixed-duration (6 months) subcutaneous mosunetuzumab for previously untreated follicular or marginal zone lymphoma on a phase 2 clinical trial (NCT04792502). Analyses included flow cytometry, cytokine profiling, and RNA-seq of isolated CD8+ T-cells with TCR repertoire inference. Early (at 3 weeks) on-treatment samples showed broad cytokine induction, CD8+ T-cell redistribution with decreased TEMRA cells and increased CD27+CD62L+ transitional effector memory-like cells, increased PD-1 and LAG-3 expression, and induction of CD8+ transcriptional programs consistent with activation, proliferation, exhaustion priming, and SREBF2-regulated cholesterol metabolism. By mid-treatment (at 3 months), activation-associated features contracted toward baseline, with no evidence of phenotypic exhaustion, though with persistent overexpression of LAG3, HAVCR2, and LAYN on RNA-seq, as well as sustained SREBF2 activation. CD8+ T-cell clonality increased at mid-treatment compared with baseline and higher clonality was associated with early clinical complete response. Mosunetuzumab also induced indirect NK-cell activation and expansion, including skewing toward CD56dimCD16bright effector state. HLA-DR upregulation on NK cells correlated with early increases in NK-activating plasma cytokines, and higher NK-cell count at mid-treatment was associated with complete response. Together, these findings define a CD8+ effector-remodeling state on mosunetuzumab therapy, characterized by clonal expansion, selective inhibitory receptor expression, sustained activation of cholesterol biosynthesis, and cytokine-linked engagement of innate immune mechanisms, providing a framework for potential strategies to support T-cell function and enhance bispecific antibody efficacy.
C. Milrod, A. Chorzalska, D. Bonal et al.· Blood Advances· 0 citations
Data for the use of rituximab, gemcitabine, and oxaliplatin (R‐GemOx) for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL) in the United States are limited. This retrospective observational study characterizes R‐GemOx treatment patterns and outcomes among patients with R/R LBCL from the nationwide, longitudinal Flatiron Health electronic health record‐derived database comprising patient‐level data primarily from US community oncology practices.
L. Budde, A. Olszewski, Bei Hu et al.· eJHaem· 0 citations
Lymphomas comprise a complex and heterogeneous group of malignancies which pose challenges in understanding their epidemiology, pathobiology, treatment responses and long-term outcomes. Evolving diagnostic classification and fast-paced therapy development compound these challenges. Robust real-world data (RWD) collection and analysis using clinical registries can contribute significantly to address gaps in understanding of practice variation and provide evidence for health technology assessments. However, to maximize the impact of lymphoma registries, and those in other diseases, there is a compelling need for global collaboration, data harmonization and automated integration between registries and other large datasets. Technologies that enable safer data sharing are already available, but historical legal frameworks and evolving privacy concerns are not keeping pace, undermining their intended purpose and limiting the full potential of available high-quality RWD to improve patient care. This White Paper written by the Global Lymphoma Registry Alliance (LyRA) discusses the importance and value of lymphoma registries for different stakeholders as well as benefits of forming a global alliance of the registry network. An alliance such as LyRA serves both academic endeavors and public interest through collaboration between patient and community organizations, policy-makers, regulatory authorities, industry and others seeking to use RWD. Bringing these stakeholders together and raising awareness more broadly will facilitate timely clinical trial result contextualization and innovation in public-private collaborations on novel trial emulations and designs, including external comparator cohorts. The LyRA leadership propose strategies for overcoming barriers to facilitate these key collaborations towards improving patient outcomes on a global scale.
Eliza A. Hawkes, E. Chung, M. Bishton et al.· Haematologica· 0 citations
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