Tumor-immune signatures of treatment resistance to brentuximab vedotin with ipilimumab and/or nivolumab in Hodgkin lymphoma.

To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin Lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA-4 and PD1. Phase 1/2, multicenter, open-label, trial NCT01896999 enrolled patients with refractory or relapsed HL (R/R HL) after one or more lines of therapy, with adequate performance status and organ function. Using peripheral blood, we assessed soluble proteins, cell composition, T cell clonality, and tumor antigen-specific antibodies in 54 patients enrolled in the phase 1 component of the trial. NCT01896999 reported high (>75%) overall objective response rates with brentuximab-vedotin (BV) in combination with ipilimumab (I) and/or nivolumab (N) in patients with R/R HL. We observed durable increase in soluble PD-1 and plasmacytoid dendritic cells as well as decreases in plasma CCL17, ANGPT2, MMP12, IL13, and CXCL13 in N-containing regimens (BV+N and BV+I+N) compared with BV+I (p<0.05). Non-responders and patients with short progression free-survival showed elevated CXCL9, CXCL13, CD5, CCL17, adenosine-deaminase, and MUC16 at baseline or after one treatment cycle and a higher prevalence of NY-ESO-1-specific autoantibodies (p<0.05). The results suggest a circulating tumor-immune-derived signature of BV±I+N treatment resistance that may be useful for patient stratification in combination checkpoint therapy.