CD40 ligation for immunotherapy of solid tumours.
Tumour vaccines provide an important focus of current cancer research and are often based on the premise that although T-cells do respond naturally to certain tumours, this is usually weak and therefore ineffective at controlling disease. An integral and necessary part of a T-cell immune response involves triggering of CD40 on antigen-presenting cells (APC) by its ligand, CD154, on responding T helper (Th) cells. Furthermore, cytotoxic responses to tumours may fail because the Th-cell response is inadequate and unable to provide CD40 stimulation of APC. Growing evidence shows that stimulating APC with soluble CD40L or an agonistic anti-CD40 mAb can, at least in part, replace the need for Th cells and generate APC that are capable of priming cytotoxic T lymphocytes (CTL). The aim of this study was to investigate whether a range of solid tumours (CD40(-)) could be treated with anti-CD40 mAb. It was found that this treatment was effective, and correlated with the intrinsic immunogenicity and aggressiveness of the tumours. The mAb could be delivered locally or at a distal site, but increased antigen load provided by irradiated tumour cells added little to the effectiveness of the treatment. T-cells were required since cytokine (interferon-gamma) and CTL activity were demonstrated following treatment and the therapeutic efficacy was lost in nude mice. In addition, depletion of CD8(+) cells abrogated protection whilst depletion of CD4(+) cells had no effect. This study demonstrates that solid CD40(-) tumours are sensitive to anti-CD40 mAb therapy and that the response bypasses the need for Th cells.
Todryk
S M
SM
Division of Oncology, St. George's Hospital Medical School, Cranmer Terrace, SW17 0RE, London, UK .
Tutt
A L
AL
Green
M H
MH
Smallwood
J A
JA
Halanek
N
N
Dalgleish
A G
AG
Glennie
M J
MJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000502:physiology; D019013:CD40 Antigens / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000628:therapy*; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens