Immunotherapy for glioblastoma: the promise of combination strategies

Abstract

Glioblastoma (GBM) treatment has remained almost unchanged for more than 20 years. The current standard of care involves surgical resection (if possible) followed by concomitant radiotherapy and chemotherapy. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. However, mostly due to the high, multifactorial immunosuppression occurring in the microenvironment, the poor knowledge of the neuroimmune system and the presence of the blood−brain barrier, the efficacy of immunotherapy in GBM is still low. Recently, new strategies for GBM treatments have employed immunotherapy combinations and have provided encouraging results in both preclinical and clinical studies. The lessons learned from clinical trials highlight the importance of tackling different arms of immunity. In this review, we aim to summarize the preclinical evidence regarding combination immunotherapy in terms of immune and survival benefits for GBM management. The outcomes of recent studies assessing the combination of different classes of immunotherapeutic agents (e.g., immune checkpoint blockade and vaccines) will be discussed. Finally, future strategies to ameliorate the efficacy of immunotherapy and facilitate clinical translation will be provided to address the unmet medical needs of GBM.

Combination of DNA Vaccine and Immune Checkpoint Blockades Improves the Immune Response in an Orthotopic Unresectable Glioblastoma Model

“…GBM is a very complex cancer to treat, due to the multifactorial immunosuppression occurring in its TME and the BBB that limits the delivery of therapeutics to the tumor site. Therefore, targeting a single arm is not enough to modify the immune landscape, as already shown in other studies where vaccines in monotherapy did not increase the immune response while combination with chemotherapy or with ICBs did [ 8 , 33 , 34 ]. Here, we combined the use of pTOP with dual blockade of PD-1 and CTLA-4.…”

“…Given the recent success of immunotherapy in aggressive cancers, these strategies are becoming increasingly explored for GBM [ 8 ]. Therapeutic cancer vaccines constitute an interesting approach to generating a strong and specific cellular immune response while inducing immune memory.…”

“…Nowadays, there is no FDA-approved immunotherapy for GBM [ 8 ]. Moreover, recent phase III clinical trials, including ICBs or therapeutic vaccines (either as monotherapies or in addition to the SOC) for GBM treatment, have failed to improve the median overall survival of patients [ 9 , 10 , 11 ].…”

“…The negligible efficacy of immunotherapy for GBM resides in multiple factors, including (i) the high invasiveness of GBM cells [ 12 ], (ii) the presence of the blood–brain barrier (BBB) impeding the efficacy of most systemic treatments [ 13 ], (iii) the highly immunosuppressive tumor microenvironment (TME) [ 14 ], (iv) the low mutation burden [ 15 ], (v) the intra- and inter-tumoral heterogeneity [ 16 , 17 ] and (vi) the lymphopenia induced by SOC and corticotherapy [ 18 ]. Given the specific features of GBM and its TME, combining different immunotherapeutic approaches is a promising strategy for overcoming GBM multifactorial immunosuppression and increase antitumor immune response [ 8 ].…”

LncRNA HOTAIR sponges miR-301a-3p to promote glioblastoma proliferation and invasion through upregulating FOSL1

“…Glioblastoma (GBM, World Health Organization grade IV glioma) remains highly lethal due to a lack of effective therapy and its inevitable recurrence [ 1 , 2 ]. Despite current aggressive first-line therapies such as maximal surgical resection, concurrent radiotherapy, adjuvant chemotherapy with temozolomide (TMZ), as well as immunotherapy, GBM recurrence is inevitable after extending survival to a median of only 14.6 months [ 1 , 3 , 4 ]. The poor prognosis and recurrence emphasize a necessity to understand the molecular characteristics of GBM and develop effective targeted molecular therapies.…”