A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy

被引:133
作者
O'Mahony, Deirdre
Morris, John C.
Quinn, Cate
Gao, Wendy
Wilson, Wyndham H.
Gause, Barry
Pittaluga, Stefania
Neelapu, Sattva
Brown, Margaret
Fleisher, Thomas A.
Gulley, James L.
Schlom, Jeffrey
Nussenblatt, Robert
Albert, Paul
Davis, Thomas A.
Lowy, Israel
Petrus, Mike
Waldmann, Thomas A.
Janik, John E.
机构
[1] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA
[2] NCI, Med Oncol Branch, Bethesda, MD 20892 USA
[3] NCI, Pathol Lab, Bethesda, MD 20892 USA
[4] NCI, Dept Lab Med, Bethesda, MD 20892 USA
[5] NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA
[6] NCI, NEI, Bethesda, MD 20892 USA
[7] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA
[8] Medarex Inc, Bloomsbury, NJ USA
关键词
D O I
10.1158/1078-0432.CCR-06-1974
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: 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. Experimental Design: 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.
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收藏
页码:958 / 964
页数:7
相关论文
共 32 条
[1]   The use of a rapid ELISPOT assay to analyze peptide-specific immune responses in carcinoma patients to peptide vs. recombinant poxvirus vaccines [J].
Arlen, P ;
Tsang, KY ;
Marshall, JL ;
Chen, A ;
Steinberg, SM ;
Poole, D ;
Hand, PH ;
Schlom, J ;
Hamilton, JM .
CANCER IMMUNOLOGY IMMUNOTHERAPY, 2000, 49 (10) :517-529
[2]   Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4 [J].
Attia, P ;
Phan, GQ ;
Maker, AV ;
Robinson, MR ;
Quezado, MM ;
Yang, JC ;
Sherry, RM ;
Topalian, SL ;
Kammula, US ;
Royal, RE ;
Restifo, NP ;
Haworth, LR ;
Levy, C ;
Mavroukakis, SA ;
Nichol, G ;
Yellin, MJ ;
Rosenberg, SA .
JOURNAL OF CLINICAL ONCOLOGY, 2005, 23 (25) :6043-6053
[3]   Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4 [J].
Beck, Kimberly E. ;
Blansfield, Joseph A. ;
Tran, Khoi Q. ;
Feldman, Andrew L. ;
Hughes, Marybeth S. ;
Royal, Richard E. ;
Kammula, Udai S. ;
Topalian, Suzanne L. ;
Sherry, Richard M. ;
Kleiner, David ;
Quezado, Martha ;
Lowy, Israel ;
Yellin, Michael ;
Rosenberg, Steven A. ;
Yang, James C. .
JOURNAL OF CLINICAL ONCOLOGY, 2006, 24 (15) :2283-2289
[4]   Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma [J].
Bendandi, M ;
Gocke, CD ;
Kobrin, CB ;
Benko, FA ;
Sternas, LA ;
Pennington, R ;
Watson, TM ;
Reynolds, CW ;
Gause, BL ;
Duffey, PL ;
Jaffe, ES ;
Creekmore, SP ;
Longo, DL ;
Kwak, LW .
NATURE MEDICINE, 1999, 5 (10) :1171-1177
[5]   A THEORY OF SELF-NONSELF DISCRIMINATION [J].
BRETSCHER, P ;
COHN, M .
SCIENCE, 1970, 169 (3950) :1042-+
[6]   A NEW MEMBER OF THE IMMUNOGLOBULIN SUPERFAMILY - CTLA-4 [J].
BRUNET, JF ;
DENIZOT, F ;
LUCIANI, MF ;
ROUXDOSSETO, M ;
SUZAN, M ;
MATTEI, MG ;
GOLSTEIN, P .
NATURE, 1987, 328 (6127) :267-270
[7]   Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: Recommendations from the prostate-specific antigen working group [J].
Bubley, GJ ;
Carducci, M ;
Dahut, W ;
Dawson, N ;
Daliani, D ;
Eisenberger, M ;
Figg, WD ;
Freidlin, B ;
Halabi, S ;
Hudes, G ;
Hussain, M ;
Kaplan, R ;
Myers, C ;
Oh, W ;
Petrylak, DP ;
Reed, E ;
Roth, B ;
Sartor, O ;
Scher, H ;
Simons, J ;
Sinibaldi, V ;
Small, EJ ;
Smith, MR ;
Trump, DL ;
Vollmer, R ;
Wilding, G .
JOURNAL OF CLINICAL ONCOLOGY, 1999, 17 (11) :3461-3467
[8]   Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas [J].
Cheson, BD ;
Horning, SJ ;
Coiffier, B ;
Shipp, MA ;
Fisher, RI ;
Connors, JM ;
Lister, TA ;
Vose, J ;
Grillo-López, A ;
Hagenbeek, A ;
Cabanillas, F ;
Klippensten, D ;
Hiddemann, W ;
Castellino, R ;
Harris, NL ;
Armitage, JO ;
Carter, W ;
Hoppe, R ;
Canellos, GP .
JOURNAL OF CLINICAL ONCOLOGY, 1999, 17 (04) :1244-1253
[9]   Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells [J].
Dave, SS ;
Wright, G ;
Tan, B ;
Rosenwald, A ;
Gascoyne, RD ;
Chan, WC ;
Fisher, RI ;
Braziel, RM ;
Rimsza, LM ;
Grogan, TM ;
Miller, TP ;
LeBlanc, M ;
Greiner, TC ;
Weisenburger, DD ;
Lynch, JC ;
Vose, J ;
Armitage, JO ;
Smeland, EB ;
Kvaloy, S ;
Holte, H ;
Delabie, J ;
Connors, JM ;
Lansdorp, PM ;
Ouyang, Q ;
Lister, TA ;
Davies, AJ ;
Norton, AJ ;
Muller-Hermelink, HK ;
Ott, G ;
Campo, E ;
Montserrat, E ;
Wilson, WH ;
Jaffe, ES ;
Simon, R ;
Yang, LM ;
Powell, J ;
Zhao, H ;
Goldschmidt, N ;
Chiorazzi, M ;
Staudt, LM .
NEW ENGLAND JOURNAL OF MEDICINE, 2004, 351 (21) :2159-2169
[10]   CD4+ CD25+ CD62+ T-regulatory cell subset has optimal suppressive and proliferative potential [J].
Fu, S ;
Yopp, AC ;
Mao, X ;
Chen, DM ;
Zhang, N ;
Chen, D ;
Mao, MW ;
Ding, YZ ;
Bromberg, JS .
AMERICAN JOURNAL OF TRANSPLANTATION, 2004, 4 (01) :65-78