A key role of T lymphocytes is to act as extrinsic tumor suppressors and thereby mediate “cancer immunosurveillance”. Furthermore, numerous studies have shown that injection of antigen (Ag)-specific T lymphocytes can cure established cancers. Two types of Ags can be targeted for T-cell based cancer immunotherapy: tumor-specific Ags (TSAs) and minor histocompatibility Ags (MiHAs). In humans and mice, the best results have been obtained with injection of MiHA-specific T cells. The remarkable efficacy of MiHA targeted cancer immunotherapy has been exploited mainly for the treatment of hematologic cancers. More than 100,000 individuals treated for hematological malignancies owe their life to the MiHA dependent graftversus- tumor (GVT) effect.
The MiHA-dependent GVT effect represents the most solid evidence that the immune system can cure cancer in humans. Nevertheless, the tremendous potential of MiHA-targeted cancer immunotherapy is not properly exploited in medicine. In current medical practice, patients with otherwise incurable hematologic cancers are transplanted with hematopoietic cells from an allogeneic HLA-matched donor. This form of MiHA based therapy is very rudimentary. First, it lacks specificity and is associated with important toxicity.
Indeed, since unselected donor T cells recognize a multitude of MiHAs (present not only on cancer cells but also on normal tissues), they cause damage to normal cells (graft-versus-host disease; GVHD). Second, it lacks potency because donor T cells are not primed (pre-activated) against specific MiHAs present on cancer cells and can therefore be tolerized (paralyzed) by tumor cells.
We have shown that injection of T cells specific for a single MiHA can cure leukemia and solid tumors in mice without causing any GVHD if i) the T cells are primed against their target MiHA prior to injection, and ii) the target MiHA is immunodominant (highly immunogenic).