gp100209-2M peptide immunization of human lymphocyte antigen-A2+ stage I-III melanoma patients induces significant increase in antigen-specific effector and long-term memory CD8+ T cells

被引:58
作者
Walker, EB
Haley, D
Miller, W
Floyd, K
Wisner, KP
Sanjuan, N
Maecker, H
Romero, P
Hu, HM
Alvord, WG
Smith, JW
Fox, BA
Urba, WJ
机构
[1] Providence Portland Med Ctr, Robert W Franz Canc Res Ctr, Earle A Chiles Res Inst, Portland, OR 97213 USA
[2] NCI, DMS, Frederick, MD 21701 USA
[3] Ludwig Inst Canc Res, Div Oncol Immunol, Lausanne, Switzerland
[4] Becton Dickinson Biosci, San Jose, CA USA
[5] Oregon Hlth & Sci Univ, Dept Mol & Microbiol & Immunol, Portland, OR 97201 USA
关键词
D O I
10.1158/1078-0432.CCR-0095-03
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Thirty-five HLA-A2(+) patients with completely resected stage I-III melanoma were vaccinated multiple times over 6 months with a modified melanoma peptide, gp100(209-2M), emulsified in Montanide adjuvant. Direct ex vivo gp100(209-2M) tetramer analysis of pre- and postvaccine peripheral blood mononuclear cells (PBMCs) demonstrated significant increases in the frequency of tetramer(+) CD8(+) T cells after immunization for 33 of 35 evaluable patients (median, 0.36%; range, 0.05-8.9%). Ex vivo IFN-gamma cytokine flow cytometry analysis of postvaccine PBMCs after brief gp100(209-2M) in vitro activation showed that for all of the patients studied tetramer(+) CD8(+) T cells produced IFN-gamma; however, some patients had significant numbers of tetramer(+) IFN-gamma(-) CD8(+)T cells suggesting functional anergy. Additionally, 8 day gp100(209-2M) in vitro stimulation (IVS) of pre- and postvaccine PBMCs resulted in significant expansion of tetramer(+) CD8(+) T cells from postvaccine cells for 34 patients, and these IVS tetramer(+) CD8(+) T cells were functionally responsive by IFN-gamma cytokine flow cytometry analysis after restimulation with either native or modified gp100 peptide. However, correlated functional and phenotype analysis of IVS-expanded postvaccine CD8(+) T cells demonstrated the proliferation of functionally anergic gp100(209-2M)- tetramer(+) CD8(+) T cells in several patients and also indicated interpatient variability of gp100(209-2M) stimulated T-cell proliferation. Flow cytometry analysis of cryopreserved postvaccine PBMCs from representative patients showed that the majority of tetramer(+) CD8(+) T cells (78.1 +/- 4.2%) had either an "effector" (CD45 RA(+)/CCR7(-)) or an "effector-memory" phenotype (CD45 RA(-)/CCR7(-)). Notably, analysis of PBMCs collected 12-24 months after vaccine therapy demonstrated the durable presence of gp100(209-2M)-specific memory CD8(+) T cells with high proliferation potential. Overall, this report demonstrates that after vaccination with a MHC class I-restricted melanoma peptide, resected nonmetastatic melanoma patients can mount a significant antigen-specific CD8(+) T-cell immune response with a functionally intact memory component. The data further support the combined use of tetramer binding and functional assays in correlated ex vivo and IVS settings as a standard for immunomonitoring of cancer vaccine patients.
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收藏
页码:668 / 680
页数:13
相关论文
共 36 条
[1]  
Aucouturier Jerome, 2002, Expert Rev Vaccines, V1, P111, DOI 10.1586/14760584.1.1.111
[2]   CCR7 expression and memory T cell diversity in humans [J].
Campbell, JJ ;
Murphy, KE ;
Kunkel, EJ ;
Brightling, CE ;
Soler, D ;
Shen, ZM ;
Boisvert, J ;
Greenberg, HB ;
Vierra, MA ;
Goodman, SB ;
Genovese, MC ;
Wardlaw, AJ ;
Butcher, EC ;
Wu, LJ .
JOURNAL OF IMMUNOLOGY, 2001, 166 (02) :877-884
[3]   Skewed maturation of memory HIV-specific CD8 T lymphocytes [J].
Champagne, P ;
Ogg, GS ;
King, AS ;
Knabenhans, C ;
Ellefsen, K ;
Nobile, M ;
Appay, V ;
Rizzardi, GP ;
Fleury, S ;
Lipp, M ;
Förster, R ;
Rowland-Jones, S ;
Sékaly, RP ;
McMichael, AJ ;
Pantaleo, G .
NATURE, 2001, 410 (6824) :106-111
[4]   Induction of long-term memory CD8+ T cells for recall of viral clearing responses against influenza virus [J].
Deliyannis, G ;
Jackson, DC ;
Ede, NJ ;
Zeng, WG ;
Hourdakis, I ;
Sakabetis, E ;
Brown, LE .
JOURNAL OF VIROLOGY, 2002, 76 (09) :4212-4221
[5]   GENERATION OF ANTI-HUMAN CD8 BETA-SPECIFIC ANTIBODIES USING TRANSFECTANTS EXPRESSING MIXED-SPECIES CD8 HETERODIMERS [J].
DISANTO, JP ;
TERRY, LA ;
FLOMENBERG, N .
JOURNAL OF IMMUNOLOGICAL METHODS, 1991, 141 (01) :123-131
[6]   Activation of natural killer T cells by α-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein [J].
Fujii, S ;
Shimizu, K ;
Smith, C ;
Bonifaz, L ;
Steinman, RM .
JOURNAL OF EXPERIMENTAL MEDICINE, 2003, 198 (02) :267-279
[7]   Phenotypic and functional separation of memory and effector human CD8(+) T cells [J].
Hamann, D ;
Baars, P ;
Rep, MHG ;
Hooibrink, B ;
KerkhofGarde, SR ;
Klein, MR ;
vanLier, RAW .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (09) :1407-1418
[8]   Evidence that human CD8+CD45RA+CD27- cells are induced by antigen and evolve through extensive rounds of division [J].
Hamann, D ;
Kostense, S ;
Wolthers, KC ;
Otto, SA ;
Baars, PA ;
Miedema, F ;
van Lier, RAW .
INTERNATIONAL IMMUNOLOGY, 1999, 11 (07) :1027-1033
[9]   Recall response to cytomegalovirus in allograft recipients - Mobilization of CD57(+), CD28(+) cells before expansion of CD57(+), CD28(-)cells within the CD8(+) T lymphocyte compartment [J].
Hazzan, M ;
Labalette, M ;
Noel, C ;
Lelievre, G ;
Dessaint, JP .
TRANSPLANTATION, 1997, 63 (05) :693-698
[10]   Comparison of adjuvant formulations for cytotoxic T cell induction using synthetic peptides [J].
Hioe, CE ;
Qiu, H ;
Chend, PD ;
Bian, ZN ;
Li, ML ;
Li, J ;
Singh, M ;
Kuebler, P ;
McGee, P ;
OHagan, D ;
Zamb, T ;
Koff, W ;
Allsopp, C ;
Wang, CY ;
Nixon, DF .
VACCINE, 1996, 14 (05) :412-418