Clinical Efficacy of Tumor Antigen-Pulsed DC Treatment for High-Grade Glioma Patients: Evidence from a Meta-Analysis

<div><p>Background</p><p>The effectiveness of immunotherapy for high-grade glioma (HGG) patients remains controversial. To evaluate the therapeutic efficacy of dendritic cells (DCs) alone in the treatment of HGG, we performed a systematic review and meta-analysis in terms of patient survival with relevant published clinical studies.</p><p>Materials and methods</p><p>A total of 409 patients, including historical cohorts, nonrandomized and randomized controls with HGG, were selected for the meta-analysis.</p><p>Results</p><p>The treatment of HGG with DCs was associated with a significantly improved one-year survival (OS) (<i>p</i><0.001) and 1.5-, 2-, 3-, 4-, and 5-year OS (<i>p</i><0.001) compared with the non-DC group. A meta-analysis of the patient outcome data revealed that DC immunotherapy has a significant influence on progression-free survival (PFS) in HGG patients, who showed significantly improved 1-,1.5-, 2-, 3- and 4-year PFS (<i>p</i><0.001). The analysis of Karnofsky performance status (KPS) demonstrated no favorable results for DC cell therapy arm (<i>p</i> = 0.23).The percentages of CD3⁺CD8⁺ and CD3⁺CD4⁺ T cells and CD16⁺ lymphocyte subset were not significantly increased in the DC group compared with the baseline levels observed before treatment (<i>p</i>>0.05), whereas CD56⁺ lymphocyte subset were significantly increased after DC treatment (<i>p</i> = 0.0001). Furthermore, the levels of IFN-γ in the peripheral blood of HGG patients, which reflect the immune function of the patients, were significantly increased after DC immunotherapy (<i>p</i><0.001).</p><p>Conclusions</p><p>Thus, our meta-analysis showed that DC immunotherapy markedly prolongs survival rates and progression-free time, enhances immune function, and improves the efficacy of the treatment of HGG patients.</p></div

Flow diagram showing record identification, screening and study inclusion process.

<p>Flow diagram showing record identification, screening and study inclusion process.</p

Forest plot for KPS before and after DC treatment.

<p>The random effects model (Mantel-Haenszel method) was used in this analysis.</p

Comparison of 0.5-, 1-, 1.5-, and 2-year progression-free survival (PFS) between the non-DC and DC groups (A); Forest plot for 3-, 4-, and 5-year PFS between the non-DC and DC groups in HGG patients (B).

<p>The fixed effects meta-analysis model (Mantel-Haenszel method) was used in this analysis.</p

Comparison of 0.5-, 1-, 1.5- and 2-year overall survival (OS) between the non-DC and DC groups (A); Forest plot for 3-, 4-, and 5-year OS between the non-DC and DC groups in HGG patients (B).

<p>The fixed-effects meta-analysis model (Mantel-Haenszel method) was used. OR, odds ratio. DC, DC-containing therapy; non-DC, non-DC-containing therapy. Each trial is represented by a square, the center of which gives the odds ratio for that trial. The size of the square is proportional to the information in that trial. The ends of the horizontal bars denote a 95% CI. The black diamond gives the overall odds ratio for the combined results of all trials.</p

Clinical information of the eligible trials for the meta-analysis.

<p>The table summarizes the patients' basic information about the tumor stage, newly or recurrent, cases, age, KPS, operative method before the immunotherapy and details of the immunotherapy including the DC, tumor antigen, and loading route. The last row is the culture conditions used for the cells. KPS: Karnofsky performance status; AIT: Autologous irradiated tumor cells; ATL: Autologous tumor lysate; HLP: HLA-1-eluted peptides; ATP: Autologous acid-eluted tumor peptides; AHT: Autologous heat-shock tumor cells; CT: Chemical therapy; RT: Radiation therapy; SR: Surgical resection; KLH: Keyhole limpet hemocyanin; PGE2: Prostaglandin E2; TNF-α: Tumor necrosis factor-α; IL-4: Interleukin-4; i.d.: intradermalvaccination; i.t.: intratumoral vaccination; s.c.:subcutaneous injection; ICH: intra-cellular hyperthermia; UK: Unknown.</p><p>Clinical information of the eligible trials for the meta-analysis.</p

Comparison of the immunological assessment of Ag-NORs and CEA expression between the CIK and non-CIK group.

<p>Summary of the significant points in the Ag-NORs and CEA expression level between the CIK group and the non-CIK group with meta-analysis. The random-effects model was used for the calculations. Ag-NORs: argyrophilic nucleolar organizer regions; CEA: carcinoembryonic antigen; Pts: patients; 95%CI: 95% confidence interval; significant difference: P value <0.05.</p><p>Comparison of the immunological assessment of Ag-NORs and CEA expression between the CIK and non-CIK group.</p

Clinical information from the eligible trials in the meta-analysis.

<p>M: median; UK: unknown; AS: advanced stage; Chemo: chemotherapy; CK: cyberknife; γK: γ-knife; NI-DC: non-impulsed DC; ATL: Autologous tumor lysate; PI-DC: peptide impulse DC; Pts: Patients. The selective data include the authors' names, year of publication, trial period, sample size per arm, regimen used, median or mean age of patients, cell preparation, CIK-based therapy treatment and information pertaining to the study design.</p><p>Clinical information from the eligible trials in the meta-analysis.</p

Forest plot comparing the toxicity and no treatment-related side effects between the CIK group and the non-CIK group.

<p>Some serious adverse effects were observed significantly less frequently in the CIK group. Due to the lack of heterogeneity, the fixed-effect model was used.</p

Comparison of OS, ORR and DCR between the non-CIK and CIK groups.

<p>Forest plot comparing the 1-, 2- and 3-year OS between the non-CIK and CIK groups.OR, odds ratio; OS, overall survival. Due to the low heterogeneity detected, the fixed-effect model was used in this OS meta-analysis. Comparison of the ORR and the DCR between the non-CIK group and CIK group. OR, odds ratio; ORR, objective response rate; DCR, disease control rate. Due to the lack of heterogeneity, the fixed-effect model was used. OS: overall survival; ORR: objective response rate; DCR: disease control rate.</p><p>Comparison of OS, ORR and DCR between the non-CIK and CIK groups.</p