Recent Advances in Oncolytic Virotherapy and Immunotherapy for Glioblastoma: A Glimmer of Hope in the Search for an Effective Therapy?

Abstract

To date, no targeted drugs, antibodies or combinations of chemotherapeutics have been demonstrated to be more efficient than temozolomide, or to increase efficacy of standard therapy (surgery, radiotherapy, temozolomide, steroid dexamethasone). According to recent phase III trials, standard therapy may ensure a median overall survival of up to 18⁻20 months for adult patients with newly diagnosed glioblastoma. These data explain a failure of positive non-controlled phase II trials to predict positive phase III trials and should result in revision of the landmark Stupp trial as a historical control for median overall survival in non-controlled trials. A high rate of failures in clinical trials and a lack of effective chemotherapy on the horizon fostered the development of conceptually distinct therapeutic approaches: dendritic cell/peptide immunotherapy, chimeric antigen receptor (CAR) T-cell therapy and oncolytic virotherapy. Recent early phase trials with the recombinant adenovirus DNX-2401 (Ad5-delta24-RGD), polio-rhinovirus chimera (PVSRIPO), parvovirus H-1 (ParvOryx), Toca 511 retroviral vector with 5-fluorocytosine, heat shock protein-peptide complex-96 (HSPPC-96) and dendritic cell vaccines, including DCVax-L vaccine, demonstrated that subsets of patients with glioblastoma/glioma may benefit from oncolytic virotherapy/immunotherapy (>3 years of survival after treatment). However, large controlled trials are required to prove efficacy of next-generation immunotherapeutics and oncolytic vectors.

Keywords: PD-L1; TTFields; bevacizumab; dendritic cell vaccine; glioma; immunotherapy; oncolytic virotherapy; radiotherapy; targeted drugs; temozolomide.

Figure 1

Timeline of phase III clinical trials in patients with newly diagnosed or recurrent glioblastoma. Almost all trials have been negative and failed to predict positive outcomes of the preceding phase II trials. α-IFN: interferon-alpha; Bevacizumab: anti-vascular endothelial growth factor (VEGF) antibody; Cediranib: an inhibitor of VEGF receptor; CIK: autologous cytokine-induced killer cells; Enzastaurin: an inhibitor of protein kinase Cβ (PKCβ, as well as PKCα, PKCγ, and PKCε at higher concentrations); IL13-PE38QQR, also known as Cintredekin besudotox: a recombinant chimeric cytotoxin composed of human interleukin 13 (IL-13) fused to a truncated, mutated form of Pseudomonas aeruginosa exotoxin A (PE38QQR); Marizomib: an irreversible proteasome inhibitor; mOS: median overall survival; Nimotuzumab: an anti-epidermal growth factor receptor (EGFR) antibody; Nivolumab: an anti-programmed cell death protein 1 (PD-1) antibody; NovoTTF-100A System™, or Optune™ generates Tumor Treating Fields (TTFields); PCV: procarbazine, lomustine, and vincristine; Rapamycin: an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase; RT: radiotherapy; Siroquine: sirolimus (rapamycin) plus hydroxychloroquine sulfate; ST: standard therapy; TMZ/ddTMZ: temozolomide/dose dense temozolomide; Toca 511: a gammaretroviral replicating vector encoding cytosine deaminase that converts the antifungal drug 5-fluorocytosine (FC) into the antineoplastic drug 5-fluorouracil (FU); VB-111: a non-replicating adenovirus 5 carrying a proapoptotic Fas-chimera transgene under the control of an endothelial cell-specific promoter; Veliparib: a poly(ADP-ribose) polymerase (PARP) 1 and 2 inhibitor. Cited literature: [1,2,3,4,21,22,23,24,25,26,27,28,29,30,31,32,33].