Tumor vaccination for malignant brain tumors

P rogress in pediatric brain tumors continues to be uneven. Whereas in tumors like medulloblastoma there continues to be exciting progress, for other types such as high-grade gliomas the prognosis continues to be bleak and no chemotherapy is of proven efficacy. For atypical teratoid/rhabdoid tumors (AT/RTs), a study by Chi earlier this year showed the first significant indication that at least in some cases this might be a chemo-curative tumor [1]. The therapy used by Chi et al. was aggressive and potentially toxic. Hence there continues to be interest in non-chemotherapy-based treatments such as immunotherapy. This interest is to an extent inspired by potential progress using this approach in pediatric neuroblastoma and in adult glioblastoma. Immunotherapy is an important part of the upfront Children’s Oncology Group neuroblastoma trial ANBL0032 and there continues to be interest in immunotherapy for this tumor [2]. However, immunotherapy for brain tumors was regarded with skepticism by many for several decades because of a prevailing notion that the brain was an immunologically privileged site [3]. There has been a gradual acceptance that the immune system plays an important part in various diseases of the brain and that the brain should be better considered as immune specialized [4]. This has lead to many groups looking at immunotherapy again both in the lab and in clinical trials overwhelmingly in adults. There is an excellent and exhaustive review both of laboratory data and such clinical trials in an article by Okada et al. [5] which we would recommend to anyone interested in this field. The article by Arden et al., in this issue of Pediatric Blood & Cancer, selected out the pediatric experience from the work of de Vleeschouwer and van Gool using dendritic cells (DCs) to present tumor antigens [4][6]. The results in childhood high-grade gliomas and AT/RT are encouraging and should lead to further trials. There are some features of the study, however, which should lead to some caution in the interpretation of the results. These children were treated over a period when Arden et al. were attempting to optimize DC vaccine therapy and therefore the treatments were not uniform. There was considerable variation in the vaccination schedule as well as some in the ex vivo preparation of the vaccination. It is not possible to be certain from this study which schedule was best although the earliest and least complicated ones appear as successful as the later ones. Many of the patients also received chemotherapy postvaccination. It is possible, as the authors speculate, that the vaccination therapy leads to an increased susceptibility to chemotherapy. However, this adds to the difficult in interpreting outcome. The numbers of children in most diagnostic categories are small, even in the largest group. Those with high-grade gliomas, the reader can see in Table II, of their manuscript are not a uniform group of tumors. If one takes the largest uniform histology group, namely glioblastoma, then there are 4 survivors out of 22 children. Three of these four have been followed more than 24 months. For the AT/RTs two out of three patients treated are long-term survivors, which is certainly impressive but the numbers are very small. However, one must remember that in the relapsed setting, both glioblastomas and AT/RT are rapidly fatal. Therefore, anything that suggests a possibility of a sustained response in these diseases should be regarded seriously, but with caution given the numbers. The authors of this editorial noted, as we are sure did the reviewers, that much of the data here appears to have been presented in another article by the same group lead by de Vleeschouwer and Van Gool [6]. Those articles, however, described a much larger cohort of patients, mostly adults. We believe it is of benefit to take out pediatric populations on such mixed aged, but ground breaking, studies. In addition, it would have been helpful if the authors had been able to confirm the diagnoses in the pediatric survivors, as misdiagnosis could be a potentially confounding factor. For the AT/ RT patients in particular a statement about INI-1 status would have been helpful and given the small number could have been easily achieved on the original paraffin blocks, using the now standard immunohistochemistry [7]. Moreover, one should be wary of dismissing the efficacy of a therapy for a particular if this is based on small numbers. By example, the authors showed only one patient out of four with ependymoma responding to immunotherapy. However, our group has data suggesting that ependymomas might be a good brain tumor to target with immunotherapy [8]. Most editorials call for more studies and this one will be no different. We would like to see a phase II study using a uniform therapy applied to a well-characterized group of children with similar histology of brain tumors at the time of recurrence. During such a study investigators would resist the temptation to improve the therapy during the life-time of the study. For example, even if more data were added to that in the literature that dural or intratumoral DC immunotherapy was better than intradermal delivery alone, as used in the clinical study by Yamanaka et al. [9], the investigators should stick to a predetermined therapeutic plan for all patients entered. A study conducted in such a manner would determine definitive outcomes and help guide us in developing future trials.