T-cell immunotherapy for malignant glioma: toward a combined approach

Abstract

Immunotherapies using T lymphocytes are now considered as promising approaches for treating malignant glioma patients. This review discusses how basic understanding of antitumor T-cell responses in the brain are now leading to the rational planning of such novel therapeutic modalities. Clinical trials show that therapeutic vaccination with defined glioma antigens or dendritic cells pulsed with glioma lysates is feasible and generally well tolerated, but clinical efficacy has yet to be demonstrated in randomized trials. Preclinical data have established that effector T cells can be engineered to more efficiently recognize tumor cells via high-affinity T-cell receptors or chimeric antibody-like receptors. Animal studies have demonstrated that glioma immunotherapy is enhanced if immunosuppressive molecules (including transforming growth factor-beta) and glioma infiltrating regulatory T cells are inactivated. Clinical trials are under way assessing transforming growth factor-beta2 antisense oligonucleotides and regulatory T cell depletion. Combination of any of the above approaches with chemotherapy or radiotherapy is strongly supported by animal and clinical observations. Future T-cell immunotherapies will combine different strategies to deliver potent T cells to the glioma bed. The synergy of immunotherapies with radiotherapy and chemotherapy requires optimization, but it is now clear that these modalities are partners and not enemies.