Table 1.
Summary of therapeutic strategies to treat GBM.
| Treatment | Biological Action | Notes |
|---|---|---|
| Image-guided Surgery | ||
| Intraoperative ultrasonography | tumor removal | Routine clinical use. Used in ORs for maximal safe resection of brain tumors since the 1980s. |
| Intraoperative MRI | tumor removal | Routine clinical use. The first iMRI system was installed in 1994 at Brigham and Women’s Hospital. |
| Intraoperative fluorescence imaging | tumor removal | New clinical use. In 2017, Gleolan® (5-aminolevulinic acid) was FDA-approved for intraoperative fluorescence imaging. |
| Chemotherapy (small Molecules) | ||
| Temozolomide | alkylates DNA base pairs | Routine clinical use. Approved by the FDA in 1999 as a monotherapy and again in 2005 for use in newly diagnosed GBM concomitantly with radiotherapy and as maintenance treatment. |
| Carmustine (BCNU) | alkylates DNA base pairs | Routine clinical use. Gliadel® wafers were approved by the FDA for recurrent GBM in 1997 and for the newly diagnosed high-grade gliomas (III and IV) in 2003. |
| Lomustine (CCNU) | alkylates DNA base pairs | Routine clinical use. FDA approved in 2014 for patients with brain tumors following surgery and/or radiotherapy. |
| Fotemustine | alkylates DNA base pairs | Approved in Europe but not in the US. Phase II clinical trials have shown therapeutic benefit in recurrent GBM. |
| Radiation therapy (RT) | ||
| 2D conventional RT | creates DNA double-strand breaks and ROS | Routine clinical use. Largely being phased out for brain RT. Still used in some instances of uncomplicated bone metastases. |
| 3D conformal RT | creates DNA double-strand breaks and ROS | Routine clinical use. Good for advanced and inoperable tumors; used post-operatively. |
| Intensity-modulated RT | creates DNA double-strand breaks and ROS | Routine clinical use as adjuvant therapy after surgical tumor resection. |
| Stereotactic radiosurgery (SRS) | creates DNA double-strand breaks and ROS | Routine clinical use with either a gamma emitter (e.g., Gamma Knife) or a linear accelerator (e.g., Cyber Knife). |
| Brachytherapy | creates DNA double-strand breaks and ROS | Clinical adoption is slow due to adverse events and risk of exposure to people in close proximity to the patient. |
| Particle RT (Proton therapy) | creates DNA double-strand breaks and ROS | FDA approved but reimbursement for the procedure is low. Phase II clinical trials are underway to evaluate the efficacy of proton versus photon irradiation (NCT02179086, NCT01854554). |
| Inhibitor Therapy | ||
| Bevacizumab (mAb) | inhibits VEGF-A | Routine clinical use. FDA approved for recurrent GBM in 2009. |
| Irinotecan (CPT-11) (small molecule) | inhibits topoisomerase I | Phase I/II trials for recurrent GBM showed mixed results. Phase II clinical trials for combination therapies are under way for recurrent and pediatric GBM (NCT04267978, NCT02192359). |
| Veliparib (ABT-888) (small molecule) | inhibits PARP | Phase II trials in adults with recurrent (NCT01026493) and new (NCT00770471, NCT02152982) GBM showed limited benefit. A phase I/II study of veliparib with RT and TMZ in children with diffuse intrinsic pontine glioma reported little to no survival benefit (NCT01514201). |
| Olaparib (AZD-2281, MK-7339) (small molecule) | inhibits PARP | Phase II trials in recurrent GBM are ongoing (NCT03212274). Olaparib exacerbated hematological toxicities when used with TMZ in patients with recurrent GBM (NCT01390571). Further studies are warranted to understand potential clinical benefit. |
| Niraparib (MK-4827) (small molecule) | inhibits PARP | A phase I trial evaluated niraparib and TMZ in advanced cancer but with few GBM patients (NCT01294735). A phase II trial evaluating niraparib with TTFs in recurrent GBM is underway (NCT04221503). May be good treatment option for tumors over-expressing EGFR. |
| Pamiparib (BGB-290) (small molecule) | inhibits PARP | Phase I/II trials are underway studying pamiparib with TMZ in new and recurrent GBM (NCT03914742, NCT03150862). |
| Cediranib (AZD-2171) (small molecule) | inhibits VEGFR | Phase II-III trials in recurrent GBM showed little to no benefit. Some studies may be underpowered or lack proper patient selection (NCT00777153, NCT01310855, NCT00305656). A phase II trial is comparing cediranib and olaparib to bevacizumab for recurrent GBM (NCT02974621). |
| Gossypol (AT-101) (small molecule) | binds with and inhibits Bcl-2, Bcl-xL and Mcl-1 | Phase II trials were performed in recurrent and new GBM (NCT00390403, NCT00540722). Very little follow-up data exists. |
| Cabozantinimb (XL-184) (small molecule) | tyrosine kinase inhibitor | Phase II trial in adult patients with recurrent GBM showed modest clinical activity (NCT00704288). Phase II trial in pediatric patients with recurrent or progressive high grade gliomas is ongoing (NCT02885324). |
| Erlotinib | EGFR inhibitor | Phase II studies in recurrent GBM as monotherapy (NCT00337883,) and in combination with other therapies (NCT00039494, NCT00445588, NCT00525525 NCT00335764). Also evaluated in new GBM (NCT00187486, NCT00720356). Clinical results have not confirmed benefit. |
| Gefitinib | EGFR inhibitor | Phase II trials in new and recurrent GBM for both adult and pediatric patients (NCT00052208, NCT00014170, NCT00025675, NCT00042991). |
| Depatuxizumab mafodotin (ABT-414) | Ab targets EGFR and drug inhibits tubulin | Phase III trial was halted when no survival benefit for new GBM patients could be demonstrated over placebo plus TMZ/radiation (NCT02573324). |
| Imatinib | multi-targeted tyrosine kinase inhibitor | Phase II trials in new and recurrent GBM showed no clinical activity. Drug has poor BBB penetration. |
| Dasatinib | multi-targeted tyrosine kinase inhibitor | Phase I/II clinical trials in recurrent GBM failed to show treatment efficacy and have been limited by toxicity, especially when used in combination with a second chemotherapy (NCT00948389, NCT00423735). |
| Sorafenib | multi-targeted protein kinase inhibitor | Clinical trials to date have not been promising. Ongoing phase I/II trial evaluating sorafenib + everolimus (NCT01434602) and sorafenib, valproic acid, and sildenafil (NCT01817751) in recurrent high grade gliomas. |
| Sunitinib | multi-targeted protein kinase inhibitor | Several phase II clinical trials have not shown anti-glioma effects. There are no ongoing clinical trials known currently. |
| Temsirolimus (CCI-779) | inhibits mTOR | Phase I/II trials as a mono- and co-therapy mostly for recurrent GBM (NCT00329719, NCT00112736, NCT00022724). Little added benefit. |
| Everolimus | inhibits mTOR | Underway: Phase II trial evaluating combination with sorafenib (NCT01434602), Phase I trial evaluating combination with ribociclib in children (NCT03355794). |
| Liposomes | ||
| 2B3–101 PEGylated liposomes | Target GSH/GSH transporters | Phase I/IIa trial to explore the preliminary antitumor activity of 2B3-101 in brain metastases or recurrent malignant glioma (NCT01386580). |
| SGT-53 Cationic liposomes | Target Scfv/TfR | Phase II trial of combined temozolomide and SGT-53 for treatment of recurrent glioblastoma (NCT02340156). |
| Liposomal irinotecan | convection enhanced delivery (CED) | Phase II trial of convection-enhanced, image-assisted delivery of liposomal-irinotecan in recurrent high grade glioma (NCT02022644). |
| Immunotherapy | ||
| Cemiplimab | checkpoint inhibitor that binds to PD-1 | Phase II trials are underway for recurrent (NCT04006119) and newly diagnosed (NCT03491683) GBM. |
| Nivolumab | checkpoint inhibitor that binds to PD-1 | Phase III trials are underway for recurrent (NCT02017717) and newly diagnosed (NCT02617589, NCT02667587) GBM. |
| Rindopepimut peptide vaccine | targets EGFR deletion mutation EGFRvIII | Phase III clinical trial is ongoing (NCT01480479). |
| DCVax®-L | DCs are primed to recognize tumor-specific antigens | Ongoing phase III clinical trial (NCT00045968). |
| VB-111 (Ofranergene obadenovec) gene therapy using an adenovirus type 5 vector | Virus carries a trans-gene for chimeric death receptor that connects Fas to hTNF receptor 1. | Phase I/II trials showed statistically significant improvement for VB-111 monotherapy in recurrent GBM (NCT01260506). Phase III trial using dual administration of VB-111 and bevacizumab failed to improve outcomes in recurrent GBM. (NCT02511405). |
| CAR T cell therapy | T cells are engineered to express receptors against specific tumor markers | There are currently 19 clinical trials listed under clinicaltrials.gov, including ongoing studies NCT04385173, NCT04077866, NCT04045847, NCT04045847, NCT04214392, NCT04003649, NCT02937844, NCT03392545, NCT02208362, NCT0338923 |
| Misc. Therapies | ||
| Laser interstitial thermal therapy (LITT) | thermal ablation of tumor tissue | Studied for its applications toward tumor therapy and treatment of radiation necrosis. Current clinical trials: NCT02970448 (Phase I: LITT + chemoradiation for new HGGs), NCT03341806 (Phase 1: LITT + avelumab for recurrent GBM), NCT04699773/ NCT04181684 (LITT + hypofractionated RT for new/recurrent GBM) |
| Tumor Treating Fields (TTF) | disrupts mitotic cell division | May be good for recurrent GBM, inoperable tumors, and/or effective supplement to chemo/radiotherapy |