title: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.
abstract: BACKGROUND
  Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.
  
  
  METHODS
  In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.
  
  
  RESULTS
  Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.
  
  
  CONCLUSIONS
  Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).
authors.affiliation: From the Mayo Clinic, Rochester, MN (S.M.A.); Memorial Sloan Kettering Cancer Center (A.M.L., D.C.) and Weill Cornell Medical College (A.M.L.) - both in New York; Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore (I.B.); University of Utah Huntsman Cancer Institute, Salt Lake City (A.H.); Oregon Health and Science University and the Knight Cancer Institute, Portland (E.C.S.); John Theurer Cancer Center, Hackensack University Medical Center, Hackensack (M.G.), and Bristol-Myers Squibb, Lawrenceville (L.Z., J.F.G., S.Y.K.) - both in New Jersey; Abramson Cancer Center, University of Pennsylvania (S.J.S.), and Fox Chase Cancer Center (M.M.M.) - both in Philadelphia; Dana-Farber Cancer Institute (G.J.F., B.C., M.A.S., P.A.) Brigham and Women's Hospital (S.J.R., A.H.L.), and Harvard Medical School (G.J.F., B.C., M.A.S., P.A., S.J.R., A.H.L.) - all in Boston; and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles (J.M.T.).
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Lesokhin
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.forename: Ahmad
authors.initials: A
authors.lastname: Halwani
authors.forename: Emma C
authors.initials: EC
authors.lastname: Scott
authors.forename: Martin
authors.initials: M
authors.lastname: Gutierrez
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Schuster
authors.forename: Michael M
authors.initials: MM
authors.lastname: Millenson
authors.forename: Deepika
authors.initials: D
authors.lastname: Cattry
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Bjoern
authors.initials: B
authors.lastname: Chapuy
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.forename: Lili
authors.initials: L
authors.lastname: Zhu
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grosso
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000079963:Brentuximab Vedotin; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000378:metabolism / Q000628:therapy; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D007167:Immunotherapy; D053612:Janus Kinases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012008:Recurrence; D016539:Reed-Sternberg Cells / Q000187:drug effects; D050791:STAT Transcription Factors / Q000378:metabolism; D033581:Stem Cell Transplantation
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D050791:STAT Transcription Factors; D000077594:Nivolumab; D000079963:Brentuximab Vedotin; D053612:Janus Kinases