Maximizing Output from Current Glioma Vaccine Trials to Construct Robust Next-Generation Immunotherapies

Abstract

standardized, defined vaccines, particularly through vaccine formulation and adjuvant selection. Indeed, basic and clinical data should be exploited to guide us towards higher efficacy vaccines testable in the near future. From a basic immunology standpoint, the sine qua non for T cell-based immunotherapy is targeting a tumor-expressed antigen. And yet we frequently attempt the impossible – we try to judge glioma vaccine efficacy after inducing immune responses to unknown antigens (e.g., those presumed to be present in tumor lysate or complexed with heat shock proteins) or by using defined peptide vaccines, but with nondefined expression by the tumor cells of each vaccinated individual [2,4]. Nevertheless, there are now major advances in defining glioma antigens expressed in vivo [5]. Moreover, there are now encouraging clinical responses to suggest that immunotherapy is sometimes ‘on target’, although not for the majority of patients. In the absence of ‘perfect’ glioma-specific antigens uniformly expressed by the tumor, there are no easy solutions for vaccine design and interpretation; we should therefore be cautious about rejecting a given vaccine formulation based on negative clinical results. The way forward will require continued use of animal models, in which much maligned model tumor antigens still play an important role when investigating vaccine potency, or the role of T-cell subsets in antiglioma immunotherapies [6]. Correlating immunological and clinical response data is a burning issue that clouds interpretation of most tumor immunotherapy studies, but the challenge is particularly demanding for gliomas because of tumor site inaccessibility. A peripherally administered vaccine will induce an antigen-specific immune response that is detectable at some stage at some site. In clinical High-grade gliomas are highly heterogeneous malignant tumors with poor prognosis, accounting for approximately 40% of primary CNS tumors. The absence of major progress with conventional treatment modalities (i.e., surgery, radiotherapy and chemotherapy) and the proven chemoand radio-resistance of glioma cells have encouraged research into immunotherapy. This is supported by developing concepts in tumor immunology and by rational immuno therapies for certain malignancies that are starting to have clinical impact [1]. However, for brain tumor immunology to progress towards brain tumor immunotherapy, it has first been necessary to debunk a number of myths and scientifically establish that: