Whole tumor cell vaccines for glioma immunotherapy.

High-grade glioma is associated with an extremely poor prognosis despite standard treatment with surgery, radiotherapy and chemotherapy. There is a pressing need to develop more effective treatments. Recent advances in immunotherapy for solid cancers have invigorated the search for an effective immunotherapy for glioma. There are many formidable obstacles such as the need to break tolerance to self-antigens and overcome tumor-induced immune suppression. Another fundamental problem is the fact that the optimum antigen targets for T-cell-based glioma immunotherapy remain unknown. Until recently, glioma immunotherapies reaching clinical translation have mainly targeted unselected antigens derived from autologous tumor tissue or defined selfantigens overexpressed in tumor relative to normal tissues (tumor-associated antigens [TAAs]). Theoretically, the ideal targets for cancer immunotherapy would be the products of tumor-specific mutations not previously encountered by the host immune system. Recent literature linking the success of checkpoint blockade in melanoma patients with responses directed at neoantigens has added weight to this idea. One described glioma neoantigen, EGFRvIII, is already at an advanced stage of assessment in clinical trials. However, with respect to glioma immunotherapy, the relative importance of targeting neoepitopes as opposed to TAA is not yet clear. Compared with other solid cancers, glioma harbors a relatively low number of mutations, reducing the likelihood of immunogenic neoepitopes [1]. Other fundamental but unresolved questions concern the optimum number and MHC restriction of the target antigens. Gliomas are highly heterogeneous and genetically unstable so that targeting a single epitope can lead to antigen-loss and immune escape. A vaccine targeting an EGFRvIII epitope successfully eliminated EGFRvIII positive cells but did not prevent the recurrence of EGFRvIII negative tumors [2]. Although targeting a single specificity in association with a strong adjuvant can lead to epitope spreading, immunotherapies that target multiple specificities simultaneously seem more likely to succeed. With respect to MHC class restriction, it is now well established that CD4 T cell help is necessary for a fully competent cytotoxic CD8 T cell response. Indeed, there is some evidence that CD4 T cells alone may be capable of mediating effective antitumor immune responses. This would suggest that the ideal cancer vaccine should incorporate both MHC class I and MHC class II-restricted epitopes. Autologous tumor cells (ATC) have long been used as a source of antigens for incorporation into vaccines for glioma patients. ATC have the potential to provide a broad range of personalized tumor antigens that includes TAA and unique neoantigens, as well as epitopes for both CD4 and CD8 T cells. Antigens derived from ATC have most commonly been loaded on to dendritic cells, which are then administered as a vaccine. However, the Whole tumor cell vaccines for glioma immunotherapy