Anti-CD40 monoclonal antibody therapy in combination with irradiation results in a CD8 T-cell-dependent immunity to B-cell lymphoma

被引:72
作者
Honeychurch, J
Glennie, MJ
Johnson, PWM
Illidge, TM
机构
[1] Gen Hosp, Sch Med, Div Canc Sci, Canc Res UK Oncol Unit, Southampton SO16 6YD, Hants, England
[2] Gen Hosp, Sch Med, Div Canc Sci, Tenovus Res Lab, Southampton SO16 6YD, Hants, England
关键词
D O I
10.1182/blood-2002-12-3717
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The mechanisms of interaction between anti-CD40 monoclonal antibody (mAb) therapy and external beam irradiation were investigated in 2 syngeneic B-cell lymphoma models. We have-established doses of anti-CD40 mAb and irradiation which, although ineffective when given singly, were capable of providing long-term protection when used in combination. Furthermore, such treatment was not only critically dependent on the dose of mAb and irradiation but also on tumor load, with greater efficacy only occurring at higher tumor burden. Using blocking antibody, the potency of treatment was shown to be totally dependent on CD8(+) T cells, with protective levels of CD8(+) cells occurring only in mice receiving the combination of anti-CD40 and irradiation. Interestingly, the ratio of T cells (CD8(+)) to tumor cells in mice receiving combination treatment was between 10 and 15 times that seen in animals given antiCD40 or irradiation alone. In vivo tracking experiments revealed a 2-phase decrease in tumor burden, the first resulting directly from the external irradiation and the second, occurring 5 days later, concomitant with the rise in tumor-specific irradiation induced an initial kill of lymphoma cells, Probably by apoptosis, which releases tumor antigens and slows the progression of the malignancy to allow generation of a curative cytotoxic T lymphocyte (CTL) response promoted by the anti-CD46 mAb. Combining irradiation with immunomodulatory mAb as described here appears to provide a powerful new approach to the management of cancer. CD8(+) cells. We suggest that the external (C) 2003 by The American Society of Hematology.
引用
收藏
页码:1449 / 1457
页数:9
相关论文
共 40 条
  • [1] Dendritic cells acquire antigen from apoptotic cells and induce class I restricted CTLs
    Albert, ML
    Sauter, B
    Bhardwaj, N
    [J]. NATURE, 1998, 392 (6671) : 86 - 89
  • [2] Barendswaard EC, 1999, J NUCL MED, V40, P1764
  • [3] Help for cytotoxic-T-cell responses is mediated by CD40 signalling
    Bennett, SRM
    Carbone, FR
    Karamalis, F
    Flavell, RA
    Miller, JFAP
    Heath, WR
    [J]. NATURE, 1998, 393 (6684) : 478 - 480
  • [4] CROSS-PRIMING FOR A SECONDARY CYTOTOXIC RESPONSE TO MINOR H-ANTIGENS WITH H-2 CONGENIC CELLS WHICH DO NOT CROSS-REACT IN CYTOTOXIC ASSAY
    BEVAN, MJ
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1976, 143 (05) : 1283 - 1288
  • [5] CHARACTERIZATION OF A NEW MURINE B-CELL LYMPHOMA
    COBB, LM
    GLENNIE, MJ
    MCBRIDE, HM
    BRECKON, G
    RICHARDSON, TC
    [J]. BRITISH JOURNAL OF CANCER, 1986, 54 (05) : 807 - 818
  • [6] THE INDUCTION OF SKIN-GRAFT TOLERANCE IN MAJOR HISTOCOMPATIBILITY COMPLEX-MISMATCHED OR PRIMED RECIPIENTS - PRIMED T-CELLS CAN BE TOLERIZED IN THE PERIPHERY WITH ANTI-CD4 AND ANTI-CD8 ANTIBODIES
    COBBOLD, SP
    MARTIN, G
    WALDMANN, H
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1990, 20 (12) : 2747 - 2755
  • [7] CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.
    Coiffier, B
    Lepage, E
    Brière, J
    Herbrecht, R
    Tilly, H
    Bouabdallah, R
    Morel, P
    Van den Neste, E
    Salles, G
    Gaulard, P
    Reyes, F
    Gisselbrecht, C
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2002, 346 (04) : 235 - 242
  • [8] Denfeld RW, 2001, J LEUKOCYTE BIOL, V69, P548
  • [9] CD40 antibody evokes a cytotoxic T-cell response that eradicates lymphoma and bypasses T-cell help
    French, RR
    Chan, HTC
    Tutt, AL
    Glennie, MJ
    [J]. NATURE MEDICINE, 1999, 5 (05) : 548 - 553
  • [10] INHIBITION OF HUMAN B-CELL LYMPHOMA GROWTH BY CD40 STIMULATION
    FUNAKOSHI, S
    LONGO, DL
    BECKWITH, M
    CONLEY, DK
    TSARFATY, G
    TSARFATY, I
    ARMITAGE, RJ
    FANSLOW, WC
    SPRIGGS, MK
    MURPHY, WJ
    [J]. BLOOD, 1994, 83 (10) : 2787 - 2794