Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End

Abstract

Glioblastomas (GBM) are the most frequent and aggressive malignant primary brain tumor and remains a therapeutic challenge: even after multimodal therapy, median survival of patients is only 15 months. Dendritic cell vaccination (DCV) is an active immunotherapy that aims at inducing an antitumoral immune response. Numerous DCV trials have been performed, vaccinating hundreds of GBM patients and confirming feasibility and safety. Many of these studies reported induction of an antitumoral immune response and indicated improved survival after DCV. However, two controlled randomized trials failed to detect a survival benefit. This raises the question of whether the promising concept of DCV may not hold true or whether we are not yet realizing the full potential of this therapeutic approach. Here, we discuss the results of recent vaccination trials, relevant parameters of the vaccines themselves and of their application, and possible synergies between DCV and other therapeutic approaches targeting the immunosuppressive microenvironment of GBM.

Research progress on dendritic cell vaccines in cancer immunotherapy

“…As the most frequent and aggressive malignant primary brain tumor, glioblastoma multiforme (GBM) has a highly fatal prognosis and disease recurrence is universal. There is no effective therapy for recurrent disease, and the median survival after relapse is 6.2 months [ 103 ]. Animal studies on glioblastoma have demonstrated that DC vaccines can reduce tumor growth, prolong survival, and induce tumor-specific IFN-γ and cytotoxic T-lymphocyte (CTL) responses associated with T cell infiltration of tumors [ 103 ].…”

“…There is no effective therapy for recurrent disease, and the median survival after relapse is 6.2 months [ 103 ]. Animal studies on glioblastoma have demonstrated that DC vaccines can reduce tumor growth, prolong survival, and induce tumor-specific IFN-γ and cytotoxic T-lymphocyte (CTL) responses associated with T cell infiltration of tumors [ 103 ]. Numerous clinical trial studies have been initiated in GBM patients and have confirmed the feasibility and safety.…”

Glioblastoma Microenvironment and Cellular Interactions

“…Dendritic cells are ubiquitarian antigen-presenting cells, which initiate and maintain immune responses in peripheral lymphoid organs. DCs engage in an antigen-specific T cell differentiation by inducing deletion, anergy or regulation of regulatory T cells (Treg) [ 246 ], followed by activation, proliferation, and differentiation to effector cells: the cytotoxic T- and helper T lymphocytes [ 247 , 248 ].…”

“…Another is based on immunological memory: a DC vaccine (DCV) can initiate an anti-tumoral T-cell response, and a selective killing of the tumor cells [ 249 , 256 ]. If theoretically, a personalized DCV can prevent a tumor recurrence [ 256 ], the clinical response to DCV immunotherapy in GBM patients is variable (from no response to significant response) [ 248 ]. However, there are promising effects of DCV, such as the Tregs reduction in relapsed patients with high-grade glioma [ 251 ].…”

“…Through several mechanisms (tolerance, anergy, senescence, and exhaustion) the GBM’s TME induces a global state of T-cell impairment: exhaustion of T cells, reduced effector functions, and increased surface expression of co-inhibitory immune checkpoints [ 255 , 257 ]. Human GBM’s TILs express the regulatory pathways of multiple immune checkpoints [ 258 ]; the checkpoint utilization is one of the several immunosuppression mechanisms shared by MDSCs and Tregs [ 248 ]. A novel mechanism of T cells inhibition in GBM is represented by T cell sequestration in the bone marrow [ 259 ].…”