A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy.
OBJECTIVE
Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.


METHODS
Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles.


RESULTS
Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.


CONCLUSIONS
Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.
O'Mahony
Deirdre
D
Metabolism Branch, Laboratory of Pathology, Department of Laboratory Medicine, National Eye Institute, Bethesda, MD 20892-1457, USA.
Morris
John C
JC
Quinn
Cate
C
Gao
Wendy
W
Wilson
Wyndham H
WH
Gause
Barry
B
Pittaluga
Stefania
S
Neelapu
Sattva
S
Brown
Margaret
M
Fleisher
Thomas A
TA
Gulley
James L
JL
Schlom
Jeffrey
J
Nussenblatt
Robert
R
Albert
Paul
P
Davis
Thomas A
TA
Lowy
Israel
I
Petrus
Mike
M
Waldmann
Thomas A
TA
Janik
John E
JE
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D019041:L-Selectin / Q000096:biosynthesis; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D017430:Prostate-Specific Antigen / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit; D019041:L-Selectin; D017430:Prostate-Specific Antigen