Vaccine-Based Immunotherapeutics for the Treatment of Glioblastoma: Advances, Challenges, and Future Perspectives.

Glioblastoma is a highly aggressive neoplasm with an extremely poor prognosis. Despite maximal gross resection and chemoradiotherapy, these grade IV astrocytomas consistently recur. Glioblastoma cells exhibit numerous pathogenic mechanisms to decrease tumor immunogenicity while promoting gliomagenesis, which manifests clinically as a median survival of less than 2 years and few long-term survivors. Recent clinical trials of vaccine-based immunotherapeutics against glioblastoma have demonstrated encouraging results in prolonging progression-free survival and overall survival. Several vaccine-based treatments have been trialed, such as peptide and heat-shock proteins, dendritic cell-based vaccines, and viral-based immunotherapy. In this literature review, we discuss the immunobiology of glioblastoma, significant current and completed vaccine-based immunotherapy clinical trials, and broad clinical challenges and future directions of glioblastoma vaccine-based immunotherapeutics.

Cuoco JA ，Benko MJ ，Busch CM ，Rogers CM ，Prickett JT ，Marvin EA ... -  《-》

[What's next in glioblastoma treatment: Tumor-targeted or immune-targeted therapies?].

Glioblastoma (GBM) is associated with a poor prognosis. This review will discuss different directions of treatment, mostly regarding immunotherapies and combinatorial approaches. Standard treatment for newly diagnosed GBM is maximal and safe surgical resection followed by concurrent radiochemotherapy (RCT) based on temozolomide, allowing 14.6 months median survival. Nowadays, no combination with molecular-targeted therapy had significantly improved prognosis. Phases I and II data are emerging, highlighting the potential efficacy of associations with other therapies. Studies have suggested the potential of targeting tumor stem cells, at less partially responsible for resistance to RCT. There is now some evidence that immunotherapy is also relevant for brain tumors. Treatment strategies have mainly explored vaccines strategies, such as the dendritic cell, heat shock protein or EGFRvIII vaccines. Of the work initiated in melanoma, immune checkpoints inhibitors have exhibited stimulating results. Others trials have demonstrated potential of autologous stimulated lymphocytes. Moreover, strong data indicates that radiation therapy has the potential to promote immunogenicity and create a sort of in situ personalized vaccine. These data provide strong evidence to support the potential of associating combinatorial targeted and/or immunotherapeutic regimens in patients with GBM that may change patient outcome.

Schernberg A ，Marabelle A ，Massard C ，Armand JP ，Dumont S ，Deutsch E ，Dhermain F ... -  《-》

Dendritic cell immunotherapy for glioblastoma.

Polyzoidis S ，Ashkan K 《-》

Current challenges in designing GBM trials for immunotherapy.

Weathers SP ，Gilbert MR 《-》

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment.

Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor and has a very poor prognosis, with only around 5% of patients surviving for a period of 5 years or more after diagnosis. Despite aggressive multimodal therapy, consisting mostly of a combination of surgery, radiotherapy, and temozolomide chemotherapy, tumors nearly always recur close to the site of resection. For the past 15 years, very little progress has been made with regards to improving patient survival. Although immunotherapy represents an attractive therapy modality due to the promising pre-clinical results observed, many of these potential immunotherapeutic approaches fail during clinical trials, and to date no immunotherapeutic treatments for GBM have been approved. As for many other difficult to treat cancers, GBM combines a lack of immunogenicity with few mutations and a highly immunosuppressive tumor microenvironment (TME). Unfortunately, both tumor and immune cells have been shown to contribute towards this immunosuppressive phenotype. In addition, current therapeutics also exacerbate this immunosuppression which might explain the failure of immunotherapy-based clinical trials in the GBM setting. Understanding how these mechanisms interact with one another, as well as how one can increase the anti-tumor immune response by addressing local immunosuppression will lead to better clinical results for immune-based therapeutics. Improving therapeutic delivery across the blood brain barrier also presents a challenge for immunotherapy and future therapies will need to consider this. This review highlights the immunosuppressive mechanisms employed by GBM cancers and examines potential immunotherapeutic treatments that can overcome these significant immunosuppressive hurdles.

Pearson JRD ，Cuzzubbo S ，McArthur S ，Durrant LG ，Adhikaree J ，Tinsley CJ ，Pockley AG ，McArdle SEB ... -  《Frontiers in Immunology》