Treatment of GBM
The WHO grade IV HGG, called glioblastoma multiforme (GBM), is the most frequent brain cancer in adults with an incidence of 3–4 per 100,000 adults per year and 2 per million children . The treatment for these patients consists primarily of maximal safe surgery in order to debulk the tumoral mass for symptomatic relief and to obtain tissue for histological diagnosis, followed by radio chemotherapy and maintenance chemotherapy to induce optimal local tumor control. In spite of improved surgery and radiotherapy, and the addition of temozolomide (TMZ) to the multimodal treatment strategy, the prognosis of patients with GBM remains poor: the median overall survival (OS) is about 15 months, with 88% of patients dying within 3 years. Relapse is universal and is believed to be due to the extensive spread of tumor cells into surrounding regions of the brain. At the time of relapse, the prognosis is particularly poor, with reports of 100% mortality within 18 months . A recent review pointed to the progression-free survival (PFS) at 6 month and median OS as most useful and accessible end points, the latter ranging between 5 and 13 months for relapsed GBM patients. The prognosis upon recurrence might be improving with the initiation of new multimodal treatment strategies. Most reports are not yet focusing on long-term survival. In spite of being an orphan disease, the tumour still causes the highest number of years of life lost due to cancer. One of the particular challenges with classical chemotherapeutic strategies is overcoming the blood–brain barrier. Therefore, preclinical research is focused on alternate approaches, such as targeted therapy including anti-angiogenesis strategies, and especially immunotherapy. Treating cancer by means of immunotherapy (e.g., cancer vaccines, adoptive cell transfer, and checkpoint blockade) has slowly evolved over decades in a nowadays clinically applicable treatment in a number of cancer types (e.g., metastatic melanoma, renal cell carcinoma, non-small cell lung cancer, prostate cancer. Active specific immunotherapy with autologous mature dendritic cells loaded with autologous tumour cell lysate is an emerging and innovative treatment approach for patients with HGG.
The preclinical and clinical results, together with clinical results obtained independently by other research teams provide a strong rationale to continue exploration of immunotherapy in patients with HGG.
Dendritic cells (DCs) are a subset of white blood cells, critical to most aspects of adaptive immunity due to their central role as specialized antigen-presenting cells (APCs) in the initiation phase of T cell responses . Typically DCs reside as immature cells in almost every organ and tissue at the interface of potential pathogen entry sites. Danger-triggered DCs start to mature: they up-regulate chemokine receptors, which guide them to draining lymph nodes. There, the mature DCs are capable of inducing primary T cell responses due to their high levels of major histocompatibility complex (MHC), adhesion and costimulatory molecule expression. As opposed to the other APC, DCs are able to present and cross-present the antigenic peptides in the context of both MHC Class II and Class I molecules, respectively. In this way, they can prime not only CD4+ T helper cells, but also CD8+ cytotoxic T cells (CTLs). Both effector cell types are believed to be necessary to induce an effective cell-mediated immune response.
Dendritic cells are not only sentinels in the adaptive immune response, but have also been shown to be strong activators of NK cells and NKT cells, thus linking the innate and adaptive immune responses. In this way, both tumour cells with and without expression of MHC class I molecules can theoretically be killed. All these particular characteristics make DCs a perfect adjuvant in active specific immunotherapeutic strategies, in which one aims to induce a specific immune response in vivo.