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Figure 1 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

Protein dynamics in HL during checkpoint blockade treatment. A, Overview of the clinical trial E4412 experimental design. Three treatment arms included: (i) BV + ipilimumab (I), (ii) BV + nivolumab (N), and (iii) BV + I + N, with participant number (n) indicated. B, Regression modeling strategy using mixed effect models applied to analyze independently four different assay methodologies. Each assay was modeled considering relevant clinical variables and adjusted for multiple testing using FDR correction. C, Summary heatmap showing the log₂-fold change (log₂FC) between time points and treatments. The changes with a positive log₂FC over time in color blue are associated with a decrease over time and red with an increase over time. The −log₁₀ (P value) is represented by the size of the circles, indicating statistical significance as the circles increase. D, Line and boxplot figures showing the changes in expression for markers increased posttreatment such as PDCD1, GMZA, PTN, CAIX, IL18, CD28, and markers decreased posttreatment such as CCL17, ANGPT2, IL13, and CXCL13. E, Summary heatmap of differential expression associated with response. The changes with a positive log₂FC in color blue are associated with a lower expression in nonresponders and red with higher expression in nonresponders. F, Line and boxplot examples of significant (P < 0.05 & FDR < 0.05) proteins associated with response (blue) or nonresponse (red) over time.

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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.