Immune biomarkers as predictors of response to mosunetuzumab in previously untreated follicular (FL) and marginal zone lymphoma (MZL).

7063 Background: CD3xCD20 bispecific antibodies (BsAbs), including mosunetuzumab, induce high rates of complete response (CR) in indolent B-cell lymphomas. However, predicting the response and understanding systemic immune changes induced by the treatment (Tx) remain unmet needs. We hypothesized that changes in circulating immune biomarkers could predict Tx response in patients (pts) receiving first-line mosunetuzumab for FL and MZL. Methods: Immune biomarkers were measured in peripheral blood samples from pts enrolled in BrUOG-401 (NCT04792502), an investigator-initiated phase 2 trial of time-limited (8 cycles [C]) mosunetuzumab Tx for untreated, high-burden FL and MZL. Disease assessments by PET/CT occurred after C4 (MidTx) and C8 (end of Tx, EOTx). Pts without MidTx CR received additional lenalidomide in C4-8 with optional Tx extension up to C12. Samples were collected at baseline (PreTx), C1 day 8 (C1D8), C2 day 1 (C2), at MidTx, and at EOTx. We measured 25 plasma cytokines related to T-cell activation and regulation using a multiplex Luminex assay, and immune cell subsets using flow cytometry. Markers were compared by rank-sum tests or mixed-effects generalized linear models. P values were not corrected for multiplicity in this exploratory study. Results: Among 34 pts evaluable for EOTx response, 29 (85%) attained EOTx CR, and 22 (65%) achieved MidTx CR. Baseline cytokine levels were available for 22 pts, of whom 19 had EOTx CR, and 15 MidTx CR. No significant association was found between PreTx cytokine levels and CR at MidTx or EOTx. At C1D8, markers of T cell activation (IL2, IL7, IFNg, GZMA/B) increased overall (all P<0.05), but only lower CTLA-4 levels significantly predicted MidTx CR (P=0.0031). Persistently lower CTLA-4 at MidTx also correlated with MidTx CR (P=0.008). No cytokine was significantly associated with EOTx CR. Flow cytometry (n=26) showed an overall increase in circulating NK cells on Tx (P<0.05 at all timepoints). Higher PreTx NK cell abundance significantly correlated with MidTx CR (P=0.043), while higher PreTx CD4+CD45RA+ (naïve helper T) cells (P=0.0035) and lower CD4+CD45RO+CD25- (memory helper) T cells (P=0.0061) were associated with EOTx CR. Increased NK (P=0.011) and HLA-DR+ NK cells (P=0.0042) at C2 also correlated with MidTx CR. Although the CD8+CD45RO+CCR7-CD27- effector memory T cell subset increased overall at MidTx (P=0.025), no CD8+ subset was predictive of CR at any timepoint. Conclusions: Although CD8+ T cells are the main effector cells engaged by mosunetuzumab, our observations in previously untreated FL/MZL suggest that increased naïve CD4+ helper T cells and NK cells PreTx, along with lower CTLA-4 levels during Tx may better predict CR. These findings suggest that cytokine-driven immune priming could influence response to BsAbs, providing a basis for future investigations of combinations therapies to enhance their efficacy.