Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma.
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.
Ansell
Stephen M
SM
Division of Hematology and Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. ansell.stephen@mayo.edu
Hurvitz
Sara A
SA
Koenig
Patricia A
PA
LaPlant
Betsy R
BR
Kabat
Brian F
BF
Fernando
Donna
D
Habermann
Thomas M
TM
Inwards
David J
DJ
Verma
Meena
M
Yamada
Reiko
R
Erlichman
Charles
C
Lowy
Israel
I
Timmerman
John M
JM
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
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab