Background: E4412 an ECOG-ACRIN sponsored phase 1/2, multicenter, open-label trial (NCT01896999) treated patients with refractory or relapsed Hodgkin lymphoma (R/R HL) with the anti-CD30 antibody-drug conjugate (ADC) brentuximab vedotin (BV) in combination with the checkpoint inhibitors targeting CTLA-4 and/or PD-1 (ipilimumab (I) and nivolumab (N). Biomarkers currently have no ability to predict which patients will maximally benefit from these therapies. We investigated the cellular and molecular mechanisms associated with these combination therapies.
Methods: Peripheral blood plasma from 54 of 61 (89%) patients evaluable for response was collected at up to 4 time points and tested for immuno-oncology soluble analytes with Olink and for antibody titers to known tumor antigens by ELISA. Matching PBMC were analyzed by CyTOF mass cytometry for major immune cell subsets and marker surface expression, and for T cell receptor diversity by Immunoseq®. Mixed effect and Cox linear models were used to identify significantly associated changes (P<0.05) related to treatment longitudinally within groups and to overall response rate (ORR) between groups.
Results: NCT01896999 reported high (>75%) ORR. Posttreatment, we observed durable increase in soluble PD-1 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). Non-responders and patients with short progression free survival showed elevated CXCL9 and MUC16 at baseline and an increase of CXCL13, CD5, CCL17 and ADA post-treatment. NY-ESO-1 autoantibodies were more frequent in non-responders (p<0.05), and expanded TCR clonotypes were increased in responders after one treatment cycle (p<0.15).
Conclusion: This data reveals differential immune activation based on treatment modality. Our data highlights potential tumor and immune derived predictive and pharmacodynamic biomarker candidates of response. 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 and in earlier lines of therapy. Prospective evaluation of these biomarkers in the Phase II component of this study, a randomized comparison of BV+N vs. BV+N+I which has completed accrual, is planned.
Catherine Diefenbach, Edgar Gonzalez-Kozlova, Diane Marie Del Valle, Hsin-Hui Huang, Opeyemi Jegede, Vanessa Barcessat, Kevin Tuballes, Geoffrey Kelly, Manishkumar Patel, Hui Xie, Jocelyn Harris, Kimberly Argueta, Kai Nie, Kai Nie, Radim Moravec, Jen Altreuter, Dzifa Yawa Duose, Brad S. Kahl, Stephen M. Ansell, Jocye Yu, Ethan Cerami, James Lindsay, Ignacio Wistuba, Seunghee Kim-Schulze, Sacha Gnjatic