Toward a glioblastoma vaccine: promise and potential pitfalls.

Despite technical improvements in neurosurgery and radiation therapy, and countless clinical trials of various chemotherapeutic regimens, the treatment of malignant gliomas remains largely suboptimal. In particular, there has been little improvement over the last two decades in the prognosis of patients with glioblastomas, the most common and deadly type of glioma. Although recent data suggest that the addition of temozolomide to radiotherapy improves long-term outcome, the overall median survival for patients with glioblastoma treated with combined therapy is still less than 15 months. Clearly, novel treatment strategies are desperately needed. In this issue of the Journal of Clinical Oncology, Steiner et al report the preliminary results of one such novel approach. These investigators explored the use of immunotherapy as an adjuvant to standard radiotherapy in patients with glioblastoma. In this trial, selected patients with glioblastoma were treated with radiotherapy followed by a vaccine consisting of autologous cells grown from their resected tumor samples and then infected with an avian paramyxovirus (Newcastle Disease Virus) used as a nonspecific immunostimulant. The vaccines were then administered every 3 to 4 weeks to a maximum of eight treatments. During the vaccination period and until tumor progression, patients received no additional treatment. Steiner et al reports an impressive median progression-free survival of 40 weeks and a median overall survival of 100 weeks, significantly better then their historical control group (26 and 49 weeks, respectively). Additionally, the 2-year survival rate in the vaccine group was 39%, compared to 4% in the control group. The investigators attribute these improved outcomes to a vaccine-mediated antitumor response. The outcomes of the patients in this trial are clearly better than one would expect from an unselected group of patients with glioblastoma, and the report by Steiner et al is therefore of potential importance. Nevertheless, the authors’ conclusion that this therapy “appears to be feasible, safe, and seems to improve the prognosis of patients with glioblastoma” is premature. Progress in medicine, and particular in cancer therapy, generally occurs in sequential and measured increments. Claims of extraordinary leaps forward, particularly for strategies that have proved unsuccessful in the past, require a careful assessment by the critical reader of both the scientific rationale for the therapy and for potential confounding variables that may have erroneously accounted for the perceived effect. Harnessing the potential of the immune system for specifically attacking tumor cells has been the holy grail of cancer therapy for decades. There have been tremendous gains in our understanding of molecular and cellular immunology that have lead to an even greater interest in tumor immunotherapy. A quick PubMed search of the term “tumor immunotherapy” returns more than 33,000 titles, most published over the last 15 years, and many demonstrating impressive results in various animal models of cancer. These exciting reports in preclinical models have unfortunately not translated to clinical successes. Although there have been several dramatic examples of the potential ability of the immune system to induce dramatic tumor regressions through the administration of large numbers of immune effector cells (“passive immunization”), there are few definitive examples of cancer vaccines (“active immunization”) having substantial clinical efficacy. Thus, the results reported by Steiner et al are unexpected. This is particularly true when one considers that immunotherapeutic approaches for CNS tumors may pose even greater challenges than for their systemic counterparts. It has long been known that the CNS is a relative immunologic sanctuary; an environment where infections and tumors may progress with relative impunity from an effective immunologic attack. The mechanistic basis for the sanctuary status of the CNS remains largely unknown, but is JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 21 NOVEMBER 1 2004