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Is there a role for vaccine-based therapy in recurrent glioblastoma?

Bloch et al. recently reported on phase II trial results with the heat-shock protein peptide complex-96 (HSPPC-96) vaccine in patients with recurrent glioblastoma (GBM).1 An editorial by Sampson et al., which generally promoted this line of investigation in GBM,2 accompanied the article. Several comments regarding the HSPPC-96 vaccine trial seem warranted. 
 
Firstly, the trial required all patients to undergo a complete or near-complete tumor resection confirmed by early postresection MRI. The requirement of minimal residual disease in the current vaccine trial recapitulates a similar paradigm in stem cell transplantation for hematologic malignancies, which is that immunologic-based anticancer therapy requires minimal tumor burden for maximum effectiveness. The eligibility requirement of complete resection necessarily limits the vaccine approach to a small subset of patients with recurrent GBM that is likely to be fewer than 15% of all patients with recurrent disease. Additionally, based on data reported by Bloch, nearly 30% of eligible patients were unable to receive treatment for a variety of reasons, predominantly insufficient tissue being acquired at the time of surgery (wherein vaccine could not be produced) and early disease progression following resective surgery. Consequently, no more than 10% of patients with recurrent GBM may be eligible for HSPPC-96 vaccine-based therapy, a factor that limits the generalizability of HSP-vaccine therapy in this setting. 
 
The necessity of a 1-month postresection interval before commencing vaccine therapy presumably reflects the time required to manufacture a tumor-specific vaccine. The difficulties with this lengthy pretreatment window following resective surgery were reflected in the 20% of patients whose disease progressed during the time period when their HSPPC-96 vaccine was being manufactured. 
 
Lastly, the survival outcomes in the current study do not appear significantly better than those seen with conventional salvage therapy for recurrent GBM utilizing, for example, lomustine or bevacizumab.3,4 Although a median progression-free survival of 19 weeks was reported, inspection of the Kaplan-Meier survival curve indicates that only 20% of patients were progression free at 6 months (the usual benchmark for determining efficacy in recurrent GBM).5 A 20% 6-month progression-free survival is not significantly different than that reported for other phase II trials in recurrent GBM. Not clear from the current trial is the emphasis on overall survival (median, 42 weeks), which likely reflects postvaccine salvage therapy. Bloch did not enumerate therapy prior to HSP vaccine and, importantly, data were not provided on postvaccine salvage therapy, thereby confounding interpretation of the current study. Furthermore, the 9 patients in whom vaccine was generated, but who progressed before receiving the vaccine, were excluded from the intent-to-treat survival analysis. 
 
These comments are not meant to diminish the significant efforts of the HSPPC-96 vaccine trial group but rather to generate discussion regarding the role of vaccine-based immunotherapy in the treatment of recurrent GBM. As the authors mention, this phase II study serves as a platform for the recently opened randomized phase II trial comparing HSPPC-96 vaccine with or without bevacizumab to bevacizumab only. This trial and the Celldex REACT trial (bevacizumab with or without the EGFRviii peptide vaccine) will determine whether vaccine-based therapies are efficacious in recurrent GBM.