Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1.

Abstract

Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action.

• Authors: Sarah Reinke, Paul J Bröckelmann, Ingram Iaccarino, Maria Garcia-Marquez, Sven Borchmann, Franziska Jochims, Michaela Kotrova, Karol Pal, Monika Brüggemann, Elena Hartmann, Stephanie Sasse, Carsten Kobe, Stephan Mathas, Martin Soekler, Ulrich Keller, Matthias Bormann, Andreas Zimmermann, Julia Richter, Michael Fuchs, Bastian von Tresckow, Peter Borchmann, Hans Schlößer, Michael von Bergwelt-Baildon, Andreas Rosenwald, Andreas Engert, Wolfram Klapper
• Journal: Blood (Blood) Vol. 136 Issue 25 Pg. 2851-2863 (12 17 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 33113552 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Antineoplastic Agents, Immunological
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Nivolumab

Topics

• Antineoplastic Agents, Immunological (administration & dosage)
• Female
• Hodgkin Disease (drug therapy, immunology, pathology)
• Humans
• Lymphocyte Activation (drug effects)
• Male
• Nivolumab (administration & dosage)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• T-Lymphocytes, Cytotoxic (immunology, pathology)
• Tumor Microenvironment (drug effects, immunology)
• Tumor-Associated Macrophages (immunology, pathology)