Delta-24–based oncolytic viruses are conditional replication adenoviruses developed to selectively infect and replicate in retinoblastoma 1 (Rb)–deficient cancer cells but not normal cell with intact Rb1 pathways. Over the years, there has been a significant evolution in the design of Delta-24 based on a better understanding of the underlying basis for infection, replication, and spread within cancer. One example is the development of Delta-24-RGD (DNX-2401), where the arginine-glycine-aspartate (RGD) domain enhances the infectivity of Delta-24 for cancer cells. DNX-2401 demonstrated objective biological and clinical responses during a phase I window of opportunity clinical trial for recurrent human glioblastoma. In long-term responders (> 3 years), there was evidence of immune infiltration (T cells and macrophages) into the tumor microenvironment with minimal toxicity. Although more in-depth analysis and phase III studies are pending, these results indicate that Delta-24–based adenovirus therapy may induce an antitumor response in glioblastoma, resulting in long-term antitumor immune response. In this review, the authors discuss the preclinical and clinical development of Delta-24 oncolytic adenoviral therapy for glioblastoma and describe structural improvements to Delta-24 that have enhanced its efficacy in vivo. They also highlight ongoing research that attempts to address the remaining obstacles limiting efficacy of Delta-24 adenovirus therapy for glioblastoma.
Chibawanye I. Ene, Juan Fueyo, and Frederick F. Lang
Bin Jiang, Dezhang Huang, Wei He, Wenqiang Guo, MM, Xin Yin, MM, Peter Forsyth, Xueqing Lun, and Zhigang Wang
The aim of this study was to demonstrate the in vivo safety and antitumor effect of a novel recombinant vesicular stomatitis virus (VSV): G protein less (GLESS)–fusion-associated small transmembrane (FAST)–VSV.
Viral infection efficiency and cell proliferation were detected using an inverted fluorescence microscope and alarmaBlue assay, respectively. To evaluate the safety of the virus, different doses of GLESS-FAST-VSV and a positive control virus (VSV∆M51) were injected into normal F344 rats and C57BL/6 mice, and each animal’s weight, survival time, and pathological changes were examined on the following day. To evaluate the efficacy of the virus, RG2 and GL261 cells were used to construct rat and mouse glioma models, respectively, via a stereotactic method. After multiple intratumoral injections of the virus, tumor growth (size) and the survival time of the animals were observed.
In vitro experiments showed that GLESS-FAST-VSV could infect and kill brain tumor cells and had less toxic effects on normal cells. After direct injection of GLESS-FAST-VSV into the animal brains, all animals tolerated the virus well, and no animal death, encephalitis, or ventriculitis was observed. In contrast, all animals that received brain injections of VSV∆M51 in the brain died. Moreover, multiple injections of GLESS-FAST-VSV in brain tumors significantly prolonged the survival of normal-immunity animals harboring brain tumors.
GLESS-FAST-VSV exhibited little neurotoxicity and could be injected directly into the tumor to effectively inhibit tumor growth and prolong the survival of normal-immunity animals, laying a theoretical foundation for the early application of such viruses in clinical trials.
Visish M. Srinivasan, Frederick F. Lang, and Peter Kan
Oncolytic viruses (OVs) have been used in the treatment of cancer, in a focused manner, since the 1990s. These OVs have become popular in the treatment of several cancers but are only now gaining interest in the treatment of glioblastoma (GBM) in recent clinical trials. In this review, the authors discuss the unique applications of intraarterial (IA) delivery of OVs, starting with concepts of OV, how they apply to IA delivery, and concluding with discussion of the current ongoing trials. Several OVs have been used in the treatment of GBM, including specifically several modified adenoviruses. IA delivery of OVs has been performed in the hepatic circulation and is now being studied in the cerebral circulation to help enhance delivery and specificity. There are some interesting synergies with immunotherapy and IA delivery of OVs. Some of the shortcomings are discussed, specifically the systemic response to OVs and feasibility of treatment. Future studies can be performed in the preclinical setting to identify the ideal candidates for translation into clinical trials, as well as the nuances of this novel delivery method.
E. Antonio Chiocca, Frederick F. Lang, and James M. Markert
Arsalaan Salehani, Sasha Howell, and Daniel Harmon
Central nervous system neurenteric cysts (NCs) represent a rare entity thought to arise from failure of the separation of endodermal and neuroectodermal elements during week 3 of embryogenesis. They account for 0.7–1.3% of all spinal cord lesions and are typically intradural extramedullary lesions located near the cervicothoracic junction. Most NCs are associated with multisystem malformation disorders, making a solitary extramedullary NC a rare entity.
A 45-year-old man presented with progressive right lower-extremity weakness and an inability to walk. Cervical spine magnetic resonance imaging demonstrated an approximately 1.6 × 1.1 × 2.7–cm, T2 hyperintense, nonenhancing, intradural, extramedullary cystic lesion at the level of C6–7 eccentric to the right with atrophy of the spinal cord. An anterior surgical approach was used for resection of the cyst in totality with C6–7 corpectomies and anterior plating and fixation from C5 to T1. Postoperatively at 1 month, the patient denied any significant neck or arm pain and demonstrated improving right lower-extremity strength, allowing some funcitonal independence.
A solitary, extramedullary cervical NC is a rare entity, with a posterior surgical approach for resection primarily described in the literature. The authors present anterior corpectomy and plating with fixation as a viable surgical approach for this rare pathology.
Umaira Saleh, Liang Hooi Lim, Ihfaz Ismail, and Nasser Abd Wahab
Craniopharyngiomas and germ cell tumors (GCTs) are both rare intracranial tumors commonly present in childhood or middle age. They share similar clinical and radiological features. GCTs commonly give rise to tumor markers in the cerebrospinal fluid, hence guiding the treatment plan.
This article reports the case of a 5-year-old boy with a large sellar and suprasellar mass with obstructive hydrocephalus. Laboratory studies showed increased beta-human chorionic gonadotrophin (β-hCG) levels in the cystic fluid, suggestive of choriocarcinoma. He underwent 3 cycles of chemotherapy but showed a poor response. Further aspiration followed by tumor debulking was performed, and histopathological examination revealed craniopharyngioma.
This case report indicates that β-hCG, commonly regarded as a specific tumor marker for choriocarcinoma, is detectable in other forms of suprasellar tumors. The authors highlight clinical and radiological features of suprasellar tumors that can be misdiagnosed as intracranial GCTs. The relevance of tumor markers and indications for histopathological confirmation are discussed.
Joshua A. Cuoco, Cara M. Rogers, and Sandeep Mittal
Glioblastoma is the most frequent primary brain tumor in adults, with a dismal prognosis despite aggressive resection, chemotherapeutics, and radiotherapy. Although understanding of the molecular pathogenesis of glioblastoma has progressed in recent years, therapeutic options have failed to significantly change overall survival or progression-free survival. Thus, researchers have begun to explore immunomodulation as a potential strategy to improve clinical outcomes. The application of oncolytic virotherapy as a novel biological to target pathogenic signaling in glioblastoma has brought new hope to the field of neuro-oncology. This class of immunotherapeutics combines selective cancer cell lysis prompted by virus induction while promoting a strong inflammatory antitumor response, thereby acting as an effective in situ tumor vaccine. Several investigators have reported the efficacy of experimental oncolytic viruses as demonstrated by improved long-term survival in cancer patients with advanced disease. Newcastle disease virus (NDV) is one of the most well-researched oncolytic viruses known to affect a multitude of human cancers, including glioblastoma. Preclinical in vitro and in vivo studies as well as human clinical trials have demonstrated that NDV exhibits oncolytic activity against glioblastoma, providing a promising avenue of potential treatment. Herein, the authors provide a detailed discussion on NDV as a mode of therapy for glioblastoma. They discuss the potential therapeutic pathways associated with NDV as demonstrated by in vitro and in vivo experiments as well as results from human trials. Moreover, they discuss current challenges, potential solutions, and future perspectives in utilizing NDV in the treatment of glioblastoma.
Nidal B. Omar, R. Timothy Bentley, David K. Crossman, Jeremy B. Foote, Jennifer W. Koehler, James M. Markert, Simon R. Platt, Daniel R. Rissi, Andy Shores, Donald Sorjonen, Amy B. Yanke, G. Yancey Gillespie, and Melissa R. Chambers
The diagnosis of glioma remains disheartening in the clinical realm. While a multitude of studies and trials have shown promise, improvements in overall survival have been disappointing. Modeling these tumors in the laboratory setting has become increasingly challenging, given their complex in situ behavior and interactions for therapeutic evasion. Dogs, particularly brachycephalic breeds, are known to spontaneously develop gliomas that resemble human gliomas both clinically and pathophysiologically, making canines with sporadic tumors promising candidates for study. Typically, survival among these dogs is approximately 2 months with palliation alone.
The authors have completed the first stage of a unique phase I dose-escalating canine clinical trial in which the safety and tolerability of M032, a nonneurovirulent oncolytic herpes simplex virus–1 vector genetically engineered to express interleukin-12, are being studied in pet dogs with gliomas undergoing maximum safe tumor resection and inoculation of the cavity with the viral infusate.
Twenty-five canine patients were enrolled between January 2018 and August 2020. One patient was electively withdrawn from the trial by its owner, and 3 did not receive the virus. For the 21 dogs that remained, 13 had high-grade gliomas, 5 had low-grade gliomas, and 3 were undetermined. According to histopathological analysis, 62% of the tumors were oligodendrogliomas. At the time of this report, the median overall survival from the date of treatment was 151 days (± 78 days). No significant adverse events attributable to M032 or dose-limiting toxicities have been observed to date.
In this largest study of oncolytic viral therapy for canine brain tumors to date, treatment with M032 did not cause harm and the combination of surgery and oncolytic viral therapy may have contributed to prolonged survival in pet dogs with spontaneous gliomas. Forthcoming in-depth radiographic, immunohistochemical, and genetic analyses will afford a more advanced understanding of how this treatment impacts these tumors and the immune system. Our goal is to utilize these findings bitranslationally to inform human studies and refine therapies that will improve outcomes in both humans and pet dogs with gliomas.
Dileep D. Monie, Archis R. Bhandarkar, Ian F. Parney, Cristina Correia, Jann N. Sarkaria, Richard G. Vile, and Hu Li
Oncolytic viruses (OVs) are a class of immunotherapeutic agents with promising preclinical results for the treatment of glioblastoma (GBM) but have shown limited success in recent clinical trials. Advanced bioengineering principles from disciplines such as synthetic and systems biology are needed to overcome the current challenges faced in developing effective OV-based immunotherapies for GBMs, including off-target effects and poor clinical responses. Synthetic biology is an emerging field that focuses on the development of synthetic DNA constructs that encode networks of genes and proteins (synthetic genetic circuits) to perform novel functions, whereas systems biology is an analytical framework that enables the study of complex interactions between host pathways and these synthetic genetic circuits. In this review, the authors summarize synthetic and systems biology concepts for developing programmable, logic-based OVs to treat GBMs. Programmable OVs can increase selectivity for tumor cells and enhance the local immunological response using synthetic genetic circuits. The authors discuss key principles for developing programmable OV-based immunotherapies, including how to 1) select an appropriate chassis, a vector that carries a synthetic genetic circuit, and 2) design a synthetic genetic circuit that can be programmed to sense key signals in the GBM microenvironment and trigger release of a therapeutic payload. To illustrate these principles, some original laboratory data are included, highlighting the need for systems biology studies, as well as some preliminary network analyses in preparation for synthetic biology applications. Examples from the literature of state-of-the-art synthetic genetic circuits that can be packaged into leading candidate OV chassis are also surveyed and discussed.
Alexander F. Haddad, Jacob S. Young, and Manish K. Aghi
The treatment for glioblastoma (GBM) has not seen significant improvement in over a decade. Immunotherapies target the immune system against tumor cells and have seen success in various cancer types. However, the efficacy of immunotherapies in GBM thus far has been limited. Systemic immunotherapies also carry with them concerns surrounding systemic toxicities as well as penetration of the blood-brain barrier. These concerns may potentially limit their efficacy in GBM and preclude the use of combinatorial immunotherapy, which may be needed to overcome the severe multidimensional immune suppression seen in GBM patients. The use of viral vectors to deliver immunotherapies directly to tumor cells has the potential to improve immunotherapy delivery to the CNS, reduce systemic toxicities, and increase treatment efficacy. Indeed, preclinical studies investigating the delivery of immunomodulators to GBM using viral vectors have demonstrated significant promise. In this review, the authors discuss previous studies investigating the delivery of local immunotherapy using viral vectors. They also discuss the future of these treatments, including the reasoning behind immunomodulator and vector selection, patient safety, personalized therapies, and the need for combinatorial treatment.