CD40 ligation for immunotherapy of solid tumours

Todryk, Stephen M., Tutt, Alison L., Green, Michael H.A., Smallwood, J.A., Halanek, Nicole, Dalgleish, Angus G. and Glennie, Martin J. (2001) CD40 ligation for immunotherapy of solid tumours. Journal of Immunological Methods, 248 (1-2), 139-147. (doi:10.1016/S0022-1759(00)00349-5).

Abstract

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-?) 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.

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