Cytokine responsiveness of CD8+ T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients

Abstract

BackgroundImmunotherapeutic approaches, such as dendritic cell (DC) vaccination, have emerged as promising strategies in the treatment of glioblastoma. Despite their promise, however, the absence of objective biomarkers and/or immunological monitoring techniques to assess the clinical efficacy of immunotherapy still remains a primary limitation. To address this, we sought to identify a functional biomarker for anti-tumor immune responsiveness associated with extended survival in glioblastoma patients undergoing DC vaccination.Methods28 patients were enrolled and treated in two different Phase 1 DC vaccination clinical trials at UCLA. To assess the anti-tumor immune response elicited by therapy, we studied the functional responsiveness of pre- and post-vaccination peripheral blood lymphocytes (PBLs) to the immunostimulatory cytokines interferon-gamma (IFN-γ) and interleukin-2 (IL-2) in 21 of these patients for whom we had adequate material. Immune responsiveness was quantified by measuring downstream phosphorylation events of the transcription factors, STAT-1 and STAT-5, via phospho-specific flow cytometry.ResultsDC vaccination induced a significant decrease in the half-maximal concentration (EC-50) of IL-2 required to upregulate pSTAT-5 specifically in CD3+CD8+ T lymphocytes (p < 0.045). Extended survival was also associated with an increased per cell phosphorylation of STAT-5 in cytotoxic T-cells following IL-2 stimulation when the median post/pre pSTAT-5 ratio was used to dichotomize the patients (p = 0.0015, log-rank survival; hazard ratio = 0.1834, p = 0.018). Patients whose survival was longer than two years had a significantly greater pSTAT-5 ratio (p = 0.015), but, contrary to our expectations, a significantly lower pSTAT-1 ratio (p = 0.038).ConclusionsOur results suggest that monitoring the pSTAT signaling changes in PBL may provide a functional immune monitoring measure predictive of clinical efficacy in DC-vaccinated patients.

The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy

“…Therefore, immunotherapy has quickly become a preferred commensurate approach, with already proven effectiveness in cancers that have been previously characterized as incurable [2, 3]. Although immunotherapy for pediatric and adult brain cancer is actively being pursued [4–6], the characterization of parameters that prognostically identify responders versus non-responders, such as the cytokine profile of cytolytic T cells [7], is a rapidly developing area of investigation.…”

Nanotechnology to augment immunotherapy for the treatment of glioblastoma multiforme

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“…Gliomas have unique mechanisms to evade the immune system, including environments loaded with immunosuppressive Tregs and decreased levels of effector CD8+ T cells, decreased expression of co-stimulatory molecules and increased expression of co-inhibitory molecules in the brain, and evasive immunosuppressive glioma cancer stem cells that avoid destruction by immune therapies [116,117]. Aforementioned combination therapies of vaccines and checkpoint blockage may help address this issue.…”

“…Lastly, the locally immunosuppressive tumor environment evades antibody therapies [116]. Gliomas have unique mechanisms to evade the immune system, including environments loaded with immunosuppressive Tregs and decreased levels of effector CD8+ T cells, decreased expression of co-stimulatory molecules and increased expression of co-inhibitory molecules in the brain, and evasive immunosuppressive glioma cancer stem cells that avoid destruction by immune therapies [116,117].…”