Quo Vadis—Do Immunotherapies Have a Role in Glioblastoma?

Abstract

The results of CheckMate-143 indicated that nivolumab is not superior to bevacizumab in patients with recurrent glioblastoma. A first-in man exploratory study evaluating EGFRvIII-specific CAR T cells for patients with newly diagnosed glioblastoma demonstrated overall safety of CAR T cell therapy and effective target recognition. A pilot study evaluating treatment with adoptively transferred CMV-specific T cells combined with a CMV-specific DC vaccine was found to be safe and resulted in increased polyclonality of CMV-specific T cells in vivo. Despite the success of immunotherapies in many cancers, clinical evidence supporting their efficacy for patients with glioblastoma is still lacking. Nevertheless, the recently published studies provide important proof-of-concept in several areas of immunotherapy research. The careful and critical interpretation of these results will enhance our understanding of the opportunities and challenges of immunotherapies for high-grade gliomas and improve the immunotherapeutic strategies investigated in future clinical trials.

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

“…Nivolumab per se displayed no survival benefits in these animals, while increasing both AXL kinase activity and GAMs' tumor infiltration. In line with these observations, a phase III clinical trial (NCT02017717) set to compare the efficacy and safety of nivolumab administered alone versus bevacizumab in patients diagnosed with recurrent glioblastoma failed to demonstrate its efficacy [19] . Immune PD-1 check point inhibitors, including nivolumab, have proven efficacy in various malignancies and the number of clinical approved indications is constantly increasing [41] .…”

“…Therefore, glioma associated myeloid cells can be envisioned as an alternative or an ancillary pharmacological target to improve the clinical outcome of current available therapies. Noteworthy, the glioblastoma microenvironment includes also other immune cells, namely regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), that concur to the establishment of an immunosuppressive environment, impairing the effector function of infiltrating T cells and natural killer cells and facilitating tumor growth [19] . Therefore, a comprehensive understanding of these different components of the patients' immune system endowed in the tumor microenvironment is necessary to develop therapeutic strategies that increase anti-tumor immunity and clinical benefits.…”

The Gut–Brain Axis, Paving the Way to Brain Cancer

“…However, three Phase I trials of chimeric antigen receptor (CAR) T cells targeting IL13Ralpha2, Her2/CMV, and EGFRvIII for recurrent glioblastoma – the most aggressive primary brain tumor, with a dismal prognosis – have shown promising results [81,82]. Nevertheless, adaptive immune resistance, immune checkpoints, and other soluble immunosuppressive molecules have been identified as major obstacles [83].…”

Triple combination immunotherapy with GVAX, anti-PD-1 monoclonal antibody, and agonist anti-OX40 monoclonal antibody is highly effective against murine intracranial glioma

“…Though toxicity was acceptable, there were no differences in overall survival, 12-month overall survival, or progressionfree survivalleading to much disappointment in the neurooncology community. 10,11 We propose that effective immunotherapy against glioblastoma is unlikely to be achieved by monotherapy, particularly by single-agent checkpoint inhibition. Glioblastoma-associated immunosuppression operates on many fronts, and overcoming it will require targeted reversal of diverse systemic and intratumoral immunodeficiencies in these patients, including lack of antigen recognition, systemic immunosuppression of T lymphocytes, and a hostile tumor microenvironment that drives local T cell dysfunction.…”