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


  • S. Reinke
  • P.J. Bröckelmann
  • I. Iaccarino
  • M. Garcia-Marquez
  • S. Borchmann
  • F. Jochims
  • M. Kotrova
  • K. Pal
  • M. Brüggemann
  • E. Hartmann
  • S. Sasse
  • C. Kobe
  • S. Mathas
  • M. Soekler
  • U. Keller
  • M. Bormann
  • A. Zimmermann
  • J. Richter
  • M. Fuchs
  • B. von Tresckow
  • P. Borchmann
  • H. Schlößer
  • M. von Bergwelt-Baildon
  • A. Rosenwald
  • A. Engert
  • W. Klapper


  • Blood


  • Blood 136 (25): 2851-2863


  • Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to anti-programmed-death-receptor-1 (PD1) treatment and characterized by scarce Hodgkin and Reed-Sternberg cells (HRSC) perpetuating a unique tumor microenvironment (TME). Whilst in solid tumors anti-PD1 effects appear largely mediated by cytotoxic CD8+ T-cells, HRSC frequently lack major histocompatibility complex expression and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical response and high interim complete response rate to anti-PD1 based 1st-line treatment was recently reported for patients with early-stage unfavorable cHL treated in the GHSG phase II NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained in NIVAHL patients before and during the first days of nivolumab 1st-line cHL therapy. Mirroring the rapid clinical response, HRSC had disappeared from the tissue within days after the first nivolumab application. The TME shows a reduction of Tr1 T-cells and PD-L1+ tumor associated macrophages (TAM) already at this early timepoint of treatment. Interestingly, neither a cytotoxic immune-response nor a clonal T-cell expansion was observed in the tumors or peripheral blood. These early changes of the TMA 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 suggestive for withdrawal of pro-survival factors rather than induction of an adaptive anti-tumor immune response as main mechanism of action.