P-235: Isatuximab as Post-ASCT Therapy in MRD-positive Patients Augments CD8 Effector T Cell Differentiation: Insights from the UKMRA Phase 3 RADAR Study

Introduction: Addition of the anti-CD38 Ab Daratumumab to lenalidomide maintenance (R) improved depth of response and PFS in the PERSEUS study. We hypothesized that this relates in part to alterations in cellular immune function in the bone marrow (BM). In the Phase 3 RADAR study, standard risk patients who are MRD-positive post-ASCT are treated on one of 4 consolidation/maintenance arms (A-D): A, R; B, R+Isatuximab (R-Isa); C, R-Bortezomib + Dex (R-BorD) consolidation (cons) followed by R; or D, R-Isa-BorD cons followed by R-Isa.

Methods: We used flow cytometric-based immune profiling with a 10-colour antibody panel on fresh BM cells to assess immune cell populations. We aimed to define the effect of Isa on the BM immune microenvironment.

Results: We analysed the immune profile of 78 patients [40 Isa-treated (B, D) and 38 non-Isa treated (A, C); median age 60, 64.1% male, 87.2% white] after 3 months of cons/main. Isa-treated patients had a larger CD3+ T cell compartment (p=0.008), with a trend to proportionately more CD8+ cells (p=0.089). Within the CD8+ population, Isa treatment was associated with a relative loss of the early differentiated CD127+ subset (p=0.013), and increase in the terminally differentiated CD57+ subset (p=0.078). T regulatory cells did not differ between Isa and non-Isa arms. We tracked changes in T cell subsets between 3 and 6 months post-ASCT in 57 patients with paired samples. In absence of Isa, post-ASCT immune reconstitution follows a normal pattern, with earlier recovery of CD8+ T cells (3m) followed by later (6m) rise in CD4+ T cells resulting in a rise in CD4:8 ratio over time (paired Wilcoxon, p< 0.0001). With the addition of Isa, the low CD4:8 ratio seen early post-ASCT persists, with maintained dominance of CD8 effectors.

NK cells express high levels of CD38 and, as expected, Isa-exposed BM contained markedly less NK cells (p< 0.001). However there was a disproportionate loss of the CD56^dimCD57+ terminally differentiated subset (p=0.001), with relative sparing of CD56^bright NK cells (p=0.122), suggesting skewing toward a less mature subset with Isa treatment. Furthermore, comparing pre- and post-treatment BMs in Isa-treated patients did not reveal the skewing over time towards the mature CD56^dim subset (p=0.6506) which was observed in the absence of Isa (p=0.005). We observed little difference on myeloid cells. Interestingly Isa-exposed BM showed a rise in NK-T Like cells (p=0.0326) which was not observed without Isa.

Conclusions: Isa treatment alters immune cell compartments post-ASCT including patterns of terminal T cell differentiation. Further work on T cell states and TCR dynamics, as well as NK function, will reveal how cons/main strategies can maximise anti-tumour immunity in the post-ASCT setting.