Temozolomide for immunomodulation in the treatment of glioblastoma

Abstract

Temozolomide is the most widely used chemotherapy for patients with glioblastoma (GBM) despite the fact that approximately half of treated patients have temozolomide resistance and all patients eventually fail therapy. Due to the limited efficacy of existing therapies, immunotherapy is being widely investigated for patients with GBM. However, initial immunotherapy trials in GBM patients have had disappointing results as monotherapy. Therefore, combinatorial treatment strategies are being investigated. Temozolomide has several effects on the immune system that are dependent on mode of delivery and the dosing strategy, which may have unpredicted effects on immunotherapy. Here we summarize the immune modulating role of temozolomide alone and in combination with immunotherapies such as dendritic cell vaccines, T-cell therapy, and immune checkpoint inhibitors for patients with GBM.

Fig. 1

Immune effects of temozolomide as an immunomodulatory agent. Temozolomide is able to affect immune function in brain tumor patients through both effects on tumor cells and direct effects on immune cells. The tumor cell death that results from temozolomide allows release of tumor antigens that can be presented by dendritic cells (DCs). Additionally, temozolomide treatment results in cytoplasmic accumulation of antigen peptides in tumor cells, allowing for better recognition by immune cells. The effects of temozolomide on host immunity includes lymphopenia. This phenomenon can be leveraged. The homeostatic lymphocyte recovery after the temozolomide-induced lymphopenia is a window during which antigen-specific T cells can be rapidly expanded. Additionally, temozolomide may deplete or expand regulatory T cells (Tregs) which are immunosuppressive depending on the dosing regimen.