The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions

Abstract

Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches.

Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication.

Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma.

Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.

Keywords: CART therapy; glioblastoma multiforme; immune checkpoint inhibitors; immunosuppressive; immunotherapy; oncolytic virus; vaccine.

Figure 1

Timeline of treatment approval for glioblastoma and landmark investigational non-approved drugs. The lower panel demonstrates Kaplan–Meier curves of three pivotal randomized controlled trials in newly diagnosed glioblastoma which led to the approval of standard of care systemic treatment including concurrent radiation and temozolomide (Stupp protocol) [7], addition of bevacizumab to Stupp protocol [10,11], and use of tumor-treating fields with Stupp protocol [8]. Despite the improvement of OS with the addition of temzolomide, bevacizumab and TTF, the overall survival remains poor (as noted by the continued drop in slope of the curves). There are no approved treatments shown to improve the survival in recurrent glioblastoma (not shown in this figure) [12]. Kaplan–Meier curves reprinted by permission from the Massachusetts Medical Society (NEJM) and American Medical Association (JAMA). N Engl J Med. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K et al., copyright © 2005. N Engl J Med. A randomized trial of bevacizumab for newly diagnosed glioblastoma. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA et al., copyright © 2014. JAMA. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs. Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial. Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B et al., copyright © 2017. Abbreviations: TMZ: temozolomide, mOS: median overall survival, mPFS: median progression free survival, RT: radiation therapy, SOC: standard of care, TTF: tumor-treating fields.

Figure 2

Proposed approaches for the improvement of glioblastoma treatment with immune checkpoint inhibitors (ICI) include timing of administration and method of delivery, patient selection, and combinatorial therapies. Panel (A) demonstrates the promising approach of administering ICI in the neo-adjuvant setting prior to surgical resection of glioblastoma and followed by adjuvant ICI [112,113]. Convection enhanced delivery of nanoparticle ICI is another method that could improve the availability and action of ICI in glioblastoma [44]. Panel (B) shows that proper patient selection for treatment with ICI could be of a clinical benefit such as patients with high tumor mutation burden due to germline deficiency affecting DNA repair mechanisms and in patients with specific mutations that could attenuate the immunosuppressive effect in the microenvironment of the tumor [84,91,92]. Panel (C) illustrates ongoing investigational combination of ICI with other novel therapies.

Figure 3

Targeting pathways and receptors involved in cell proliferation, aggressiveness, invasion, and angiogenesis in glioblastoma. Some of the pharmaceuticals which have been trialed to target these specific receptors or pathways are illustrated.