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Glioblastoma immunotherapy: time for hope?
Giacomo Sferruzza & Gaetano Finocchiaro
Neurological Sciences (2023)Cite this article
The DCVax-L study has recently shown a significant survival gain in glioblastoma (GBM) patients treated with dendritic cell (DC) immunotherapy versus an externally controlled cohort [1]. The initial case–control design of the study required modification partly because patients in the original control arm underwent apheresis and requested their cells to be used for immunotherapy at recurrence.
Notably, 79% of patients screened were excluded for different reasons (GBM diagnosis not confirmed, insufficient amount of tumor lysate for DC preparation but also disease progression or clinical deterioration) [2], raising concerns about biases.
The potential of external controls has been discussed by the Clinical Trials Think Tank of the Society of Neuro-Oncology with caveats on possible biases [3]. Part of these caveats was addressed by Liau et al. in their statistical analysis plan. To investigate this further, we compared the PFS data of control arms of included trials and DCVax-L patients, all treated by standard radiochemotherapy. We digitally scanned the published KM curves and reconstructed survival data from curve drops relative to the number of patients at risk (https://doi.org/10.1186/1471-2288-12-9).
The median PFS (mPFS) of the reconstructed curves was compared to the original studies, confirming the accuracy of the method. The control arm of the DCVax-L trial was analyzed against the pulled control arms of the comparator randomized clinical trials using the log-rank test and the R statistical package, version 4.0.3. The mPFS of control patients of the DCVax-L trial was 7.6 months (95% CI: 5.6–11.1; 5.6–10.9 months reported in the trial), compared with 6.0 months of the pooled control arms (95% CI: 5.6–5.7) (p-value?=?0.14; Fig. 1), not supporting the hypothesis of selection bias.
Fig. 1
figure 1
PFS of control patients treated by the standard of care (Stupp regimen) in the DCVax-L trial and control patients with the same treatment in the external trials used as comparators
Full size image
In the DCVax-L study, the survival advantage associated with DC vaccination is significant in GBM with MGMT methylation and at recurrence. We previously found a statistically significant co-occurrence of MGMT methylation and hypermutations [4] and a significant increase in CD8?+?T cells in GBM with increased mutational burden [5]. Indeed, some patients in the DCVax-L study with MGMT methylation may have benefited from DC immunotherapy because of increased persistent mutational burden and CD8?+?T cell density [6], but the hypothesis cannot be tested because of the lack of data on immune responses. Nevertheless, the long-awaited results of this study may give some hope to GBM patients and encourage further testing on the use of external data in clinical trials.
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