CD40 ligation for immunotherapy of solid tumours

Tumour vaccines provide an important focus of current cancer research and a re often based on the premise that although T-cells do respond naturally to certain tumours, this is usually weak and therefore ineffective at control ling disease. An integral and necessary part of a T-cell immune response in volves 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 t o 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 wh ether a range of solid tumours (CD40(-)) could be treated with anti-CD40 mA b. It was found that this treatment was effective, and correlated with the intrinsic immunogenicity and aggressiveness of the tumours. The mAb could b e delivered locally or at a distal site, but increased antigen load provide d by irradiated tumour cells added little to the effectiveness of the treat ment. T-cells were required since cytokine (interferon-gamma) and CTL activ ity were demonstrated following treatment and the therapeutic efficacy was lost in nude mice. In addition, depletion of CD8(+) cells abrogated protect ion 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. (C) 2001 Elsevier Science B.V . All rights reserved.