Using Oncolytic Viruses to Treat Brain Tumors: Advances in Clinical Trials
Alissar Dalloul
Traditional treatments for brain tumors, such as surgery, chemotherapy, and radiotherapy, are often limited by several physiological barriers: the blood-brain barrier prevents many drugs from effectively reaching tumor tissue, and brain tumors often develop resistance to these conventional therapies. Moreover, these treatments can damage any surrounding healthy brain tissue, potentially leading to significant neurological side effects.
Amidst this dilemma, oncolytic virotherapy offers a promising therapeutic strategy, harnessing genetically engineered viruses to overcome challenges within the tumor’s immunosuppressive microenvironment (TME): to selectively infect and destroy cancer cells while sparing normal tissue. These viruses, known as oncolytic viruses (OVs), are designed to replicate preferentially within tumor cells, causing them to burst — a process called oncolysis. The release of viral particles and tumor antigens from destroyed cells triggers the body’s immune system to recognize and attack remaining cancer cells, thereby transforming the tumor microenvironment from immunosuppressive to immunostimulatory.
In addition to these direct cytotoxic effects, however, OVs can be engineered to deliver therapeutic genes, stimulate immune checkpoint pathways, and work synergistically with other treatments such as immunotherapy and radiation. As such, given their ability to combine direct tumor lysis with immune activation, OVs have been increasingly viewed as a promising vessel for treating aggressive and recurring brain tumors — including glioblastoma multiforme (GBM).
These OVs include adenovirus, herpesvirus, vaccinia virus, and parvovirus, and this review discusses clinical trials involving these OVs, highlighting their mechanisms, safety profiles, and potential to promote tumor remission.
Adenovirus
Adenovirus, one of the first clinically studied OVs, promotes strengthened antitumor immunity by entering tumor cells, activating transcription, and selectively replicating within the tumor microenvironment (Lawler et al., 2017; Wang et al., 2021).
A leading approach in adenovirus engineering involves combining adenovirus with checkpoint inhibitors to enhance antitumor effects and safety (Nassiri et al., 2023; Yang et al., 2021). A 2023 study assessed this combination by measuring the intratumoral delivery of the modified adenovirus DNX-2401 and, subsequently, levels of the anti-PD-1 antibody pembrolizumab in glioblastoma — used as a readout of activated T-cell immune response in tumor cells. The study found that although the objective response rate was not statistically higher than the control rates, the safety profile and survival endpoints were achieved (Nassiri et al., 2023).
Moreover, a 2022 study evaluated the oncolytic adenovirus DNX-2401 for treating diffuse intrinsic pontine glioma (DIPG). The researchers used a “targeted approach,” infusing DNX-2401 directly into the tumor site through a catheter placed in the cerebellar peduncle, followed by radiotherapy (Gállego Pérez-Larraya et al., 2022). The study reported promising results, including changes in T-cell activity, enhanced immune cell responses, and reductions or stabilization of tumor size in some patients (Gállego Pérez-Larraya et al., 2022).
Herpesvirus
Herpesviruses possess strong lytic properties, which, when combined with genetic modifications that confer replicative specificity, promote systemic antitumor immunity (Lawler et al., 2017). For instance, deleting Infected Cell Protein 6 in herpesvirus enables selective replication in cells with p15 inactivation — a common feature in tumor cells (Lawler et al., 2017).
Clinical trials for glioma have explored various modified herpesviruses, including unarmed strains, armed strains, and strains engineered for tumor-receptor-specific viral entry (Nguyen and Saha, 2021). Unarmed herpesviruses — though highly safe — exhibit only modest efficacy (Nguyen and Saha, 2021). In contrast, armed strains — enhanced with cytokines, angiogenesis inhibitors, or programmed death-1pathway inhibitors — demonstrate higher efficacy by boosting antitumor immune responses and overcoming tumor-mediated immunosuppression (Nguyen and Saha, 2021). For example, arming herpesvirus with IL-12 cytokine stimulates the cytotoxicity of cells, limiting tumor spread (Nguyen and Saha, 2021). Lastly, modifying herpes viruses for tumor-receptor-specific viral entry improves cancer selectivity and effectiveness against glioblastoma multiforme tumors, and has been particularly effective when combined with cancer-targeting therapies (Nguyen and Saha, 2021).
Studies have especially assessed the efficacy of the third-generation, triple-mutated herpes simplex virus type 1 G47∆ (Todo et al., 2022). In one leading approach, G47∆ was delivered intratumorally in six doses to adults with residual or recurrent supratentorial glioblastoma after prior radiation therapy; the primary efficacy endpoint in this study was met (Todo et al., 2022). Long-term findings in the majority of study participants included increased lymphocytes and tumor infiltration (Todo et al., 2022). Despite adverse effects such as vomiting and leukopenia, the survival benefit and acceptable safety profile supported approval of G47∆ in Japan.
Vaccinia
Vaccinia virus, best known for its use in the smallpox vaccine, is a cytoplasmic DNA virus that has primarily been used in combination with radiation therapy (Lawler et al., 2017). In a mouse glioblastoma study, treatment with a genetically modified vaccinia virus, combined with radiation therapy, resulted in tumor remission in 67% of the mice. Notably, 62% of these cures were resistant to recurrent cancer (Storozynsky et al., 2023).
Like other OVs, vaccinia virus can selectively replicate and express genes in tumor tissue but not in normal tissue. Due to safety concerns about uncontrolled viral replication, researchers are developing replication-controllable strains of viruses. One approach involves deleting the native vaccinia tk gene and inserting the herpesvirus tk gene, rendering the virus sensitive to the drug ganciclovir as a built-in safety switch (Islam et al., 2020). The HSV-tk-armed candidate OTS-412, when combined with Ganciclovir, has demonstrated promising antitumor effects while providing controllable safety mechanisms for tumor selectivity (Islam et al., 2020).
Parvovirus
Parvovirus used in oncolytic virotherapy induces selective tumor cell death and reverses tumor-mediated immune suppression. The H-1 parvovirus (H-1PV) strain targets and kills malignant cells through oncolysis, while also activating antitumor immune responses (Angelova et al., 2021). In preclinical studies, rat H-1PV has demonstrated oncolytic properties, including selective replication, activation of diverse cell death pathways, and immunogenic cell death that triggers T-cell reactions (Bretscher et al., 2019; Geletneky et al., 2017).
In clinical studies, rat H-1PV has been shown to successfully cross the blood-brain/blood-tumor barrier, spread within tumors through a selective replication, and elicit antitumor immune responses (Getelenky et al. 2017). Moreover, H-1PV has demonstrated tumor-suppressive effects in preclinical glioma models (Angelova et al., 2021). Although H-1PV is a promising therapy, more research is needed. For example, a better understanding of the H-1PV life cycle could strengthen combination strategies, such as combining H-1PV virotherapy with radiation therapy, which has already shown signs of improved remission and survival after recurrence (Angelova, Ferreira, Bretscher, Rommelaere, & Marchini, et al., 2021).
Commentary
OVs in clinical trials have demonstrated the potential to overcome challenges in the tumor’s immunosuppressive microenvironment, from disrupting tumor cell growth to enhancing the efficacy of cancer-targeting therapies. Furthermore, unlike some immunotherapies, which may lose efficacy over time, virotherapy shows promise for recurrent brain cancer (Storozynsky et al., 2023). Taken together, trials underscore OVs as a viable treatment option for brain tumors and support continued investment in research on primary brain tumors.
About the Author
Alissar Dalloul ('27) is a junior at Harvard College concentrating in neuroscience/mind, brain, and behavior.
References
Amidst this dilemma, oncolytic virotherapy offers a promising therapeutic strategy, harnessing genetically engineered viruses to overcome challenges within the tumor’s immunosuppressive microenvironment (TME): to selectively infect and destroy cancer cells while sparing normal tissue. These viruses, known as oncolytic viruses (OVs), are designed to replicate preferentially within tumor cells, causing them to burst — a process called oncolysis. The release of viral particles and tumor antigens from destroyed cells triggers the body’s immune system to recognize and attack remaining cancer cells, thereby transforming the tumor microenvironment from immunosuppressive to immunostimulatory.
In addition to these direct cytotoxic effects, however, OVs can be engineered to deliver therapeutic genes, stimulate immune checkpoint pathways, and work synergistically with other treatments such as immunotherapy and radiation. As such, given their ability to combine direct tumor lysis with immune activation, OVs have been increasingly viewed as a promising vessel for treating aggressive and recurring brain tumors — including glioblastoma multiforme (GBM).
These OVs include adenovirus, herpesvirus, vaccinia virus, and parvovirus, and this review discusses clinical trials involving these OVs, highlighting their mechanisms, safety profiles, and potential to promote tumor remission.
Adenovirus
Adenovirus, one of the first clinically studied OVs, promotes strengthened antitumor immunity by entering tumor cells, activating transcription, and selectively replicating within the tumor microenvironment (Lawler et al., 2017; Wang et al., 2021).
A leading approach in adenovirus engineering involves combining adenovirus with checkpoint inhibitors to enhance antitumor effects and safety (Nassiri et al., 2023; Yang et al., 2021). A 2023 study assessed this combination by measuring the intratumoral delivery of the modified adenovirus DNX-2401 and, subsequently, levels of the anti-PD-1 antibody pembrolizumab in glioblastoma — used as a readout of activated T-cell immune response in tumor cells. The study found that although the objective response rate was not statistically higher than the control rates, the safety profile and survival endpoints were achieved (Nassiri et al., 2023).
Moreover, a 2022 study evaluated the oncolytic adenovirus DNX-2401 for treating diffuse intrinsic pontine glioma (DIPG). The researchers used a “targeted approach,” infusing DNX-2401 directly into the tumor site through a catheter placed in the cerebellar peduncle, followed by radiotherapy (Gállego Pérez-Larraya et al., 2022). The study reported promising results, including changes in T-cell activity, enhanced immune cell responses, and reductions or stabilization of tumor size in some patients (Gállego Pérez-Larraya et al., 2022).
Herpesvirus
Herpesviruses possess strong lytic properties, which, when combined with genetic modifications that confer replicative specificity, promote systemic antitumor immunity (Lawler et al., 2017). For instance, deleting Infected Cell Protein 6 in herpesvirus enables selective replication in cells with p15 inactivation — a common feature in tumor cells (Lawler et al., 2017).
Clinical trials for glioma have explored various modified herpesviruses, including unarmed strains, armed strains, and strains engineered for tumor-receptor-specific viral entry (Nguyen and Saha, 2021). Unarmed herpesviruses — though highly safe — exhibit only modest efficacy (Nguyen and Saha, 2021). In contrast, armed strains — enhanced with cytokines, angiogenesis inhibitors, or programmed death-1pathway inhibitors — demonstrate higher efficacy by boosting antitumor immune responses and overcoming tumor-mediated immunosuppression (Nguyen and Saha, 2021). For example, arming herpesvirus with IL-12 cytokine stimulates the cytotoxicity of cells, limiting tumor spread (Nguyen and Saha, 2021). Lastly, modifying herpes viruses for tumor-receptor-specific viral entry improves cancer selectivity and effectiveness against glioblastoma multiforme tumors, and has been particularly effective when combined with cancer-targeting therapies (Nguyen and Saha, 2021).
Studies have especially assessed the efficacy of the third-generation, triple-mutated herpes simplex virus type 1 G47∆ (Todo et al., 2022). In one leading approach, G47∆ was delivered intratumorally in six doses to adults with residual or recurrent supratentorial glioblastoma after prior radiation therapy; the primary efficacy endpoint in this study was met (Todo et al., 2022). Long-term findings in the majority of study participants included increased lymphocytes and tumor infiltration (Todo et al., 2022). Despite adverse effects such as vomiting and leukopenia, the survival benefit and acceptable safety profile supported approval of G47∆ in Japan.
Vaccinia
Vaccinia virus, best known for its use in the smallpox vaccine, is a cytoplasmic DNA virus that has primarily been used in combination with radiation therapy (Lawler et al., 2017). In a mouse glioblastoma study, treatment with a genetically modified vaccinia virus, combined with radiation therapy, resulted in tumor remission in 67% of the mice. Notably, 62% of these cures were resistant to recurrent cancer (Storozynsky et al., 2023).
Like other OVs, vaccinia virus can selectively replicate and express genes in tumor tissue but not in normal tissue. Due to safety concerns about uncontrolled viral replication, researchers are developing replication-controllable strains of viruses. One approach involves deleting the native vaccinia tk gene and inserting the herpesvirus tk gene, rendering the virus sensitive to the drug ganciclovir as a built-in safety switch (Islam et al., 2020). The HSV-tk-armed candidate OTS-412, when combined with Ganciclovir, has demonstrated promising antitumor effects while providing controllable safety mechanisms for tumor selectivity (Islam et al., 2020).
Parvovirus
Parvovirus used in oncolytic virotherapy induces selective tumor cell death and reverses tumor-mediated immune suppression. The H-1 parvovirus (H-1PV) strain targets and kills malignant cells through oncolysis, while also activating antitumor immune responses (Angelova et al., 2021). In preclinical studies, rat H-1PV has demonstrated oncolytic properties, including selective replication, activation of diverse cell death pathways, and immunogenic cell death that triggers T-cell reactions (Bretscher et al., 2019; Geletneky et al., 2017).
In clinical studies, rat H-1PV has been shown to successfully cross the blood-brain/blood-tumor barrier, spread within tumors through a selective replication, and elicit antitumor immune responses (Getelenky et al. 2017). Moreover, H-1PV has demonstrated tumor-suppressive effects in preclinical glioma models (Angelova et al., 2021). Although H-1PV is a promising therapy, more research is needed. For example, a better understanding of the H-1PV life cycle could strengthen combination strategies, such as combining H-1PV virotherapy with radiation therapy, which has already shown signs of improved remission and survival after recurrence (Angelova, Ferreira, Bretscher, Rommelaere, & Marchini, et al., 2021).
Commentary
OVs in clinical trials have demonstrated the potential to overcome challenges in the tumor’s immunosuppressive microenvironment, from disrupting tumor cell growth to enhancing the efficacy of cancer-targeting therapies. Furthermore, unlike some immunotherapies, which may lose efficacy over time, virotherapy shows promise for recurrent brain cancer (Storozynsky et al., 2023). Taken together, trials underscore OVs as a viable treatment option for brain tumors and support continued investment in research on primary brain tumors.
About the Author
Alissar Dalloul ('27) is a junior at Harvard College concentrating in neuroscience/mind, brain, and behavior.
References
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- Bretscher, C., & Marchini, A. (2019). H-1 parvovirus as a cancer-killing agent: Past, present, and future. Viruses, 11(6), 562.
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- Storozynsky, Q. T., Agopsowicz, K. C., Noyce, R. S., Bukhari, A. B., Han, X., Snyder, N., Umer, B. A., Gamper, A. M., Godbout, R., Evans, D. H., & Hitt, M. M. (2023). Radiation combined with oncolytic vaccinia virus provides pronounced antitumor efficacy and induces immune protection in an aggressive glioblastoma model. Cancer letters, 562, 216169. https://doi.org/10.1016/j.canlet.2023.216169
- Todo, T., Ito, H., Ino, Y., & Ohtsu, H. (2022). Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial. Nature Medicine, 28, 1630–1639.
- Wang, X., Zhong, L., & Zhao, Y. (2021). Oncolytic adenovirus: A tool for reversing the tumor microenvironment and promoting cancer treatment (Review). Oncology Reports, 45(4), 49.
- Yang, L., Gu, X., Yu, J., Ge, S., & Fan, X. (2021). Oncolytic virotherapy: From bench to bedside. Frontiers in Cell and Developmental Biology, 9, Article 790.