Editorial on “Heat Shock Protein Peptide Complex-96 (HSPPC-96) Vaccination for Recurrent Glioblastoma: A Phase II, Single Arm Trial”

In this issue of Neuro-oncology, Bloch et al, report the results of an exciting, multi-center, open label, Phase II trial in adult patients with surgically resectable GBM who are given a heat shock protein peptide complex – 96 vaccine after gross total resection. Forty-one patients were treated in this single-arm trial. A median of 6 doses of the vaccine were given. Greater than 90% of the patients were alive at 6 months, and almost 30% were alive at 12 months. The median overall survival was 42.6 weeks. Only minimal toxicities were observed, unlike the toxicity that can be observed in some less specific immunotherapy approaches.1–4 These results will now be validated in a randomized Phase II trial sponsored by the NCI (Figure 1). A number of additional findings of interest are also reported in the trial. For example, they report that patients with lymphocyte counts below the cohort median demonstrated decreased overall survival. Perhaps this is expected based on previous results showing that in some patients the lymphocyte counts, particularly in the CD4 compartment, are extremely low – similar to patients with AIDs, in fact.5,6 Conversely, others have demonstrated the value of lymphopenia, which can be induced by therapeutic temozolomide, if followed by lymphocyte homeostatic proliferation. It is important to differentiate these two phenomena. A decreased lymphocyte count at baseline probably relates to the level of immunosuppression in these patients. However, cyclic induction of lymphopenia can, in fact, boost immune responses based on the well-known phenomena of homeostatic proliferation.7–10 During this recovery phase, lymphocytes that recognize their cognate antigen and are stimulated by cytokines, such as interleukin (IL)-7 and IL-15 which are produced in response to lymphopenia, will preferentially expand. In this context, the presence of a vaccinating antigen can preferentially enhance vaccine-induced immune responses. This has been shown for both vaccines targeting T cells and B cells. A number of other caveats must also be remembered in interpreting this study. First of all, one should not conclude much from the observation that patients receiving more vaccines lived longer. This will always be true as some patients will progress or die before receiving the full complement of vaccine. Similar caveats exist when patients are not started on therapy at equivalent time points. Patients who are much further from their time of initial diagnosis are a selected population who will always have longer overall survival times from diagnosis. Secondly, imaging criteria for tumor progression in post-surgical trials needs to be carefully considered. It is very difficult to assess progression when small rims of enhancement may persist after surgical resection. This has been highlighted previously in the literature.11 Finally, and specific to this trial, one must consider that of the 68 patients screened, only 41 were enrolled, which may limit the applicability of this approach. However it is likely that as familiarity with the technology increases, screening will become more efficient, and patient selection will be optimized. Still, even at this rate, this therapy will be applicable to many more patients than some other promising therapies.9,12 Despite these caveats the results presented here are indeed impressive and form the basis for a randomized Phase II study sponsored by the NCI and presently open for enrollment through the ALLIANCE and RTOG cooperative groups (Fig. 1). In this study patients with recurrent GBM will undergo surgical resection, and their resected tumor will be sent for vaccine purification. Once vaccine has been manufactured, patients will be randomized to one of three arms, including two experimental arms that combine vaccine with bevacizumab (either concurrently or in sequence), and a third arm that represents present day standard of care treatment with bevacizumab as a single agent. This study will also offer opportunities for validation of biomarkers based on immune monitoring and improved imaging criteria for progression – both are badly needed in the field. The authors of this manuscript should be congratulated on their collaborative efforts to move this complex therapy forward and potentially deliver a very promising therapy to patients in desperate need of new approaches.