Comparison of Glioma-associated Antigen Peptide-loaded Versus Autologous Tumor Lysate-loaded Dendritic Cell Vaccination in Malignant Glioma Patients

Abstract

Summary Dendritic cell (DC) vaccination is emerging as a promising therapeutic option for malignant glioma patients. However, the optimal antigen formulation for loading these cells has yet to be established. The objective of this study was to compare the safety, feasibility, and immune responses of malignant glioma patients on two different DC vaccination protocols. 28 patients were treated with autologous tumor lysate (ATL)-pulsed DC vaccination, while 6 patients were treated with glioma-associated antigen (GAA) peptide-pulsed DCs. Safety, toxicity, feasibility and correlative immune monitoring assay results were compared between patients on each trial. Due to HLA subtype restrictions on the GAA-DC trial, 6/15 screened patients were eligible for treatment, while 28/32 patients passed eligibility screening for the ATL-DC trial. Elevated frequencies of activated natural killer (NK) cells were observed in the peripheral blood from GAA-DC patients compared with the ATL-DC patients. In addition, a significant correlation was observed between decreased regulatory T lymphocyte (Treg) ratios (post/pre vaccination) and overall survival (OS; p=0.004) in patients on both trials. In fact, Treg ratios were independently prognostic for OS in these patients, while tumor pathology was not in multivariate analyses. In conclusion, these results suggest that ATL-DC vaccination is associated with wider patient eligibility compared with GAA-DC vaccination. Decreased post/pre-vaccination Treg ratios and decreased frequencies of activated NK cells were associated with prolonged survival in patients from both trials, suggesting that these lymphocyte subsets may be relevant immune monitoring endpoints for immunotherapy protocols in malignant glioma patients.

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

“…8,9 In addition, other approaches including vaccines that decrease the frequency and function of Tregs have also shown limited clinical benefits for cancer patients. 10,11 However, the role of Tregs in human CRC patients is still controversial. [12][13][14][15][16] Given the inconsistent results concerning the prognostic value of Tregs in patients with CRC, it is not surprising that there is to date no clinical trial reporting effective immunotherapies targeting Tregs in CRC.…”

Induction of antigen-specific cytotoxic T-cell response by dendritic cells generated from ecto-mesenchymal stem cells infected with an adenovirus containing the MAGE-D4a gene

“…Research regarding brain tumor immunology has resulted in the development of novel immunotherapy strategies, including cytotoxic T-lymphocyte therapies and dendritic cell (DC) vaccines (5,6). In pediatric patients with glioma, DC-based immunotherapies may exert certain clinical benefits, particularly in individuals with minimal residual disease; however, additional investigation of such treatment is necessary (7)(8)(9). Unconventional treatment options, including gene therapy combined with immunocyte-based immunotherapy, also offer potential therapeutic approaches to reduce glioma-associated mortality (10).…”

Poor survival in glioblastoma patients is associated with early signs of immunosenescence in the CD4 T-cell compartment after surgery

“…However, GBM lysates used for dendritic cell vaccination result in expansion of HCMV-specific T cells in patients, and HCMV pp65-specific T cells recognize and kill autologous GBM cells. [40][41][42] These observations provide indisputable immunological evidence that GBM cells express HCMV peptides. HCMV peptides expressed in GBM cells may thus in theory provide a chronic antigen stimulation, which may trigger expansion of CD4 C T cells that express CD57 and later lose CD28 expression; this T cell phenotype was highly associated with HCMV infection.…”