Association of plasma cytokines with clinical benefit. A, C, and E, PFS survival analysis shows the Kaplan–Meier curves for VEGFR2, CXCL9, and MUC16, respectively. Statistics using log-rank test and Cox proportional hazard models are shown. Higher than median VEGFR2 levels were associated with slower progression whereas higher than median levels of CXCL9 and MUC16 were associated with faster progression. B, D, and F, Forest plots for VEGFR2, CXCL9, and MUC16, respectively. Here, we show the multivariate statistics for each of these proteins including sex, age, treatment type, and cancer stage (Ann Arbor stage). These figures verify the directionality of the KM curves shown and show that these three proteins are independent of these clinically relevant covariates. G, Shows the receiver operating characteristic (ROC) curves for the prediction of PFS using VEGFR2, MUC16, CXCL9, PDL1, and clinical variables. Ordered from most relevant to least relevant model, reflected on the AUC values. H, Univariate PFS Cox modeling of Olink analytes. I, Univariate OS Cox modeling of Olink analytes. Both I and H, show on the x-axis the HR and the y-axis shows the −log10 (P values) based on the log-rank test.
ARTICLE ABSTRACT
To investigate the cellular and molecular mechanisms associated with targeting CD30-expressing Hodgkin lymphoma (HL) and immune checkpoint modulation induced by combination therapies of CTLA4 and PD1, we leveraged Phase 1/2 multicenter open-label trial NCT01896999 that enrolled patients with refractory or relapsed HL (R/R HL). 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 a durable increase in soluble PD1 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). Nonresponders 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.
Identification of multi-omic immune markers from peripheral blood may help elucidate resistance mechanisms to checkpoint inhibitor and antibody–drug conjugate combinations with potential implications for treatment decisions in relapsed HL.
