title: Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
abstract: OBJECTIVE
  The growth of non-Hodgkin lymphomas can be influenced by tumor-immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen antitumor immune responses. Blocking anti-CTLA-4 monoclonal antibodies improves host resistance to immunogenic tumors, and the anti-CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers.
  
  
  METHODS
  We did a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg x 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly x 4 months (dose level 2).
  
  
  RESULTS
  Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Two patients had clinical responses; one patient with diffuse large B-cell lymphoma had an ongoing complete response (>31 months), and one with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T-cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy.
  
  
  CONCLUSIONS
  Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted.
authors.affiliation: Division of Hematology and Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. ansell.stephen@mayo.edu
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Ansell
authors.forename: Sara A
authors.initials: SA
authors.lastname: Hurvitz
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Koenig
authors.forename: Betsy R
authors.initials: BR
authors.lastname: LaPlant
authors.forename: Brian F
authors.initials: BF
authors.lastname: Kabat
authors.forename: Donna
authors.initials: D
authors.lastname: Fernando
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Habermann
authors.forename: David J
authors.initials: DJ
authors.lastname: Inwards
authors.forename: Meena
authors.initials: M
authors.lastname: Verma
authors.forename: Reiko
authors.initials: R
authors.lastname: Yamada
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: John M
authors.initials: JM
authors.lastname: Timmerman
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060908:CTLA-4 Antigen; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab