TY - JOUR
T1 - Tumor-Immune Signatures of Treatment Resistance to Brentuximab Vedotin with Ipilimumab and/or Nivolumab in
AU - Gonzalez-Kozlova, Edgar
AU - Huang, Hsin Hui
AU - Jagede, Opeyemi A.
AU - Tuballes, Kevin
AU - Del Valle, Diane M.
AU - Kelly, Geoffrey
AU - Patel, Manishkumar
AU - Xie, Hui
AU - Harris, Jocelyn
AU - Argueta, Kimberly
AU - Nie, Kai
AU - Barcessat, Vanessa
AU - Moravec, Radim
AU - Altreuter, Jennifer
AU - Duose, Dzifa Y.
AU - Kahl, Brad S.
AU - Ansell, Stephen M.
AU - Yu, Joyce
AU - Cerami, Ethan
AU - Lindsay, James R.
AU - Wistuba, Ignacio I.
AU - Kim-Schulze, Seunghee
AU - Diefenbach, Catherine S.
AU - Gnjatic, Sacha
N1 - Publisher Copyright:
©2024 The Authors; Published by the American Association for Cancer Research.
PY - 2024/7
Y1 - 2024/7
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85198933872
U2 - 10.1158/2767-9764.CRC-24-0252
DO - 10.1158/2767-9764.CRC-24-0252
M3 - Article
C2 - 38934093
AN - SCOPUS:85198933872
SN - 2767-9764
VL - 4
SP - 1726
EP - 1737
JO - Cancer research communications
JF - Cancer research communications
IS - 7
ER -