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Figure 4 from Tumor-Immune Signatures of Treatment Resistance to Brentuximab Vedotin with Ipilimumab and/or Nivolumab in Hodgkin Lymphoma

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posted on 2024-07-15, 12:00 authored by Edgar Gonzalez-Kozlova, Hsin-Hui Huang, Opeyemi A. Jagede, Kevin Tuballes, Diane M. Del Valle, Geoffrey Kelly, Manishkumar Patel, Hui Xie, Jocelyn Harris, Kimberly Argueta, Kai Nie, Vanessa Barcessat, Radim Moravec, Jennifer Altreuter, Dzifa Y. Duose, Brad S. Kahl, Stephen M. Ansell, Joyce Yu, Ethan Cerami, James R. Lindsay, Ignacio I. Wistuba, Seunghee Kim-Schulze, Catherine S. Diefenbach, Sacha Gnjatic

Cancer antigen detection and T-cell clonal dynamics associated with treatment and response. A, Heatmap showing cancer antigen detection by ELISA for all samples. The color represents the log₁₀ scale antibody titers. Positive detection is considered above levels of 2 (pink), whereas negative detection is represented by the color black. The top rows of the figure show the treatment group, best overall response, and time. The figure is separated into nonresponders (left) and responders (right). Each column box is hierarchically clustered for simplicity. B, Pie charts showing the association of NY-ESO-1 presence (left column) and nondetection (middle column). Boxplots (right column) show all titer levels for nonresponders and responders. C, Boxplots showing the standardized absolute clonal diversity index calculated using Immunarch R package. The clonal diversity changes are shown over four time points (Baseline, C2D1, Restaging, and off-study) per treatment arm. The P value from the Wilcoxon rank test is shown on top of the boxes. The y-axis is identical for all three treatment arms. There was no statistical difference between the treatments due to the observed large variances (patient heterogeneity). D, Boxplots showing an increase in clonal overlap over time for all three treatments. P values were estimated using the Wilcoxon rank test. E, Clonal expansion was stratified into unique and expanded clones (black and orange, respectively). The stacked barplot shows the average percent of each clonal expansion class over time and per treatment arm. There were no statistical differences identified between treatment arms. F, Boxplots showing the percent abundance of only expanded clones shown for responders and nonresponders over time. There were no significant differences between these two groups except for C2D1 using the Wilcoxon rank test. G, Clonal diversity boxplots comparing responders and nonresponders. Overall, responders had a higher diversity, yet it did not reach statistical significance.

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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.