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

Authors

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

Publication Date

7-1-2024

Journal

Cancer Research Communications

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.

Significance: 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.

Keywords

Humans, Brentuximab Vedotin, Hodgkin Disease, Nivolumab, Ipilimumab, Drug Resistance, Neoplasm, Female, Male, Antineoplastic Combined Chemotherapy Protocols, Adult, Middle Aged, Aged, Young Adult

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Associated Data

PMID: 38934093