Dendritic cell immunizations alone or combined with low doses of interleukin-2 induce specific immune responses in melanoma patients

被引:83
作者
Escobar, A
López, M
Serrano, A
Ramirez, M
Pérez, C
Aguirre, A
González, R
Alfaro, J
Larrondo, M
Fodor, M
Ferrada, C
Salazar-Onfray, F
机构
[1] Univ Chile, Fac Med, ICBM, Inst Biomed Sci,Programa Disciplinario Inmunol, Santiago, Chile
[2] Univ Chile, Clin Hosp, Blood Bank Serv, Santiago, Chile
[3] Univ Chile, Clin Hosp, Dept Med, Santiago, Chile
关键词
antigen presentation; cancer vaccines; dendritic cells; melanoma;
D O I
10.1111/1365-2249.2005.02938.x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Dendritic cell (DC)-based therapy has proved to be effective in patients with a variety of malignancies. However, an optimal immunization protocol using DCs and the best means for delivering antigens has not yet been described. In this study, 20 patients with malignant melanoma in stages III or IV were vaccinated with autologous DCs pulsed with a melanoma cell lysate, alone (n = 13) or in combination with low doses of subcutaneous (s.c.)interleukin (IL)-2 injections (n = 7), to assess toxicity, immunological and clinical responses. Monocyte-derived DCs were morphological, phenotypic and functionally characterized in vitro. Peripheral blood mononuclear cells (PBMC), harvested from patients either prior to and after the treatment, were analysed using enzyme-linked immunosorbent spot (ELISPOT). After vaccination, 50% of the patients tested (seven of 13) from the first group and (three of seven) from the second, showed an increase in interferon (IFN)-gamma production in response to allogeneic melanoma cell lines but not to controls. Four of five tested human leucocyte antigen (HLA)-A2(+) patients with anti-melanoma activity also showed specific T cell responses against peptides derived from melanoma-associated antigens. Delayed type IV hypersensitivity reaction (DTH) against melanoma cell lysate was observed in six of 13 patients from the group treated with DC vaccines only and four of seven from the group treated with the combination of DCs and IL-2. Significant correlations were found between DTH-positive responses against tumour lysate and both disease stability and post-vaccination survival on the stage IV patients. There were no toxicities associated with the vaccines or evidence of autoimmunity including vitiligo. Furthermore, no significant enhancement was observed as a result of combining DC vaccination with IL-2. Our data suggest that autologous DCs pulsed with tumour lysate may provide a standardized and widely applicable source of melanoma specific antigens for clinical use. It is safe and causes no significant side effects and has been demonstrated to be partially efficient at triggering effective anti-melanoma immunity.
引用
收藏
页码:555 / 568
页数:14
相关论文
共 50 条
[1]  
Baar J, 1999, Oncologist, V4, P140
[2]  
Banchereau J, 2001, CANCER RES, V61, P6451
[3]   Dendritic cells and the control of immunity [J].
Banchereau, J ;
Steinman, RM .
NATURE, 1998, 392 (6673) :245-252
[4]   Large-scale generation of mature monocyte-derived dendritic cells for clinical application in cell factories™ [J].
Berger, TG ;
Feuerstein, B ;
Strasser, E ;
Hirsch, U ;
Schreiner, D ;
Schuler, G ;
Schuler-Thurner, B .
JOURNAL OF IMMUNOLOGICAL METHODS, 2002, 268 (02) :131-140
[5]   Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo [J].
Boczkowski, D ;
Nair, SK ;
Snyder, D ;
Gilboa, E .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 184 (02) :465-472
[6]   The novel differentiation of human blood mononuclear cells into CD1a-negative dendritic cells is stimulated in the absence of exogenous cytokines by an extract prepared from pinecones [J].
Bradley, WG ;
Widen, RH ;
Weiser, AM ;
Powers, JJ ;
Fountain, LB ;
Punjwani, P ;
Lofgren, SM ;
Hadzic, T ;
Klein, R ;
Green, WH ;
Tanaka, A .
INTERNATIONAL IMMUNOPHARMACOLOGY, 2003, 3 (02) :209-223
[7]   Regulatory activity of autocrine IL-10 on dendritic cell functions [J].
Corinti, S ;
Albanesi, C ;
la Sala, A ;
Pastore, S ;
Girolomoni, G .
JOURNAL OF IMMUNOLOGY, 2001, 166 (07) :4312-4318
[8]   Phenotypical and functional characterization of clinical grade dendritic cells [J].
de Vries, IJM ;
Eggert, AAO ;
Scharenborg, NM ;
Vissers, JLM ;
Lesterhuis, WJ ;
Boerman, OC ;
Punt, CJA ;
Adema, BJ ;
Figdor, CG .
JOURNAL OF IMMUNOTHERAPY, 2002, 25 (05) :429-438
[9]  
Dunbar PR, 1999, J IMMUNOL, V162, P6959
[10]   Human monocyte isolation methods influence cytokine production from in vitro generated dendritic cells [J].
Elkord, E ;
Williams, PE ;
Kynaston, H ;
Rowbottom, AW .
IMMUNOLOGY, 2005, 114 (02) :204-212