Gene Therapy + Chemoradiotherapy for Glioblastoma

Overseen By David S. Baskin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: The Methodist Hospital Research Institute

Must not be taking: Immunosuppressants, Immunotherapy

Disqualifiers: Liver disease, Alcohol abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

62 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for glioblastoma and anaplastic astrocytoma, types of brain cancer. It combines gene therapy (ADV/HSV-tk) with standard treatments like radiotherapy and chemotherapy to assess safety and effectiveness. Participants will receive gene therapy during surgery, followed by medication and radiotherapy. This trial targets individuals newly diagnosed with these brain cancers who have not yet undergone radiation or chemotherapy and are expected to live at least 12 more weeks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have had any chemotherapy, radiotherapy, or immunotherapy within 3 weeks of starting the study. Also, you cannot be on immunosuppressive drugs, except for steroids for brain swelling.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ADV/HSV-tk, a type of gene therapy, has a promising safety record in clinical trials. In earlier studies with patients who had recurring glioblastoma, the treatment was generally well-tolerated, with fewer severe side effects compared to other treatments.

Another study found that combining ADV/HSV-tk with other therapies, such as nivolumab (a common cancer treatment), was safe. This combination did not cause many serious health problems for patients. While researchers continue to study this gene therapy, these results suggest it is a well-tolerated option for people with aggressive brain tumors like glioblastoma and anaplastic astrocytoma. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for glioblastoma?

Unlike the standard treatments for glioblastoma, which typically involve surgery, radiation, and chemotherapy, the new approach with ADV/HSV-tk introduces a unique gene therapy element. This treatment uses a modified virus to deliver a gene that makes cancer cells more susceptible to an antiviral drug, valacyclovir. Researchers are excited about this innovative mechanism because it targets cancer cells more precisely, potentially improving the effectiveness of existing treatments while minimizing damage to healthy cells. Additionally, the possibility of re-administering the gene therapy after six months offers a novel way to manage the condition over time.

What evidence suggests that ADV/HSV-tk gene therapy could be an effective treatment for glioblastoma?

Research has shown that ADV/HSV-tk gene therapy, which participants in this trial may receive, could be a promising treatment for glioblastoma, a type of brain cancer. Studies have found that patients receiving this treatment live longer without the cancer worsening and have an overall longer survival time. This gene therapy uses a virus to target cancer cells, making them more vulnerable to antiviral drugs, which helps destroy the cancer cells. Comparisons with other treatments have found this method to be similarly safe and effective. It offers a potential new option for people with aggressive brain tumors like glioblastoma. ^{1 3 6 7 8}

Who Is on the Research Team?

David S Baskin, MD

Principal Investigator

Houston Methodist Neurological Institute

Are You a Good Fit for This Trial?

This trial is for adults with newly diagnosed glioblastoma or anaplastic astrocytoma, confirmed by biopsy. Participants must have a life expectancy of at least 12 weeks, be able to provide biopsies, and not have multifocal disease or brainstem involvement. They should not be on immunosuppressive drugs (except steroids), have liver disease, alcohol misuse/abuse in the past year, known allergies to treatment components, trouble swallowing pills, other active malignancies (with exceptions), untreated infections or severe drug abuse.

Inclusion Criteria

I am using effective birth control methods.

I can have a second HSV-tk treatment after 6 months.

My biopsy shows I have a specific brain tumor without it spreading in my brain.

Exclusion Criteria

I am under 18 years old.

I have not recently had chemotherapy, radiation, immunotherapy, or experimental drugs.

Active IV drug abuse or severe opioid abuse

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery and Initial Treatment

HSV-tk gene therapy is injected during surgery, followed by valacyclovir for 14 days

2 weeks

1 visit (in-person)

Radiotherapy and Chemotherapy

Radiotherapy administered over 30 sessions (6 weeks) with concurrent chemotherapy

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment with MRI or CT every 6-8 weeks for the first year, then every 12-14 weeks

Up to 60 months

Optional Second Treatment

Participants can receive a second treatment of HSV-tk after 6 months

Not specified

What Are the Treatments Tested in This Trial?

Interventions

• ADV/HSV-tk

Trial Overview The study tests the safety and effectiveness of gene therapy using ADV/HSV-tk combined with valacyclovir medication, radiotherapy (XRT), and chemotherapy in patients who are newly diagnosed with glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA).

How Is the Trial Designed?

Group I: Experimental: ADV/HSV-tk (gene therapy) Experimental Treatment 1 Intervention

Experimental: ADV/HSV-tk (gene therapy) The gene therapy investigational product, HSV-tk will be injected during the surgery. Within 24 hours valacyclovir will be given for 14 days. Radiotherapy will be administered over 30 sessions (over 6 weeks) starting within 9 days of surgery. Standard of care/routine chemotherapy will be started concurrent with the radiotherapy dependent on patient status based on best clinical judgment following the Stupp protocol. Patient can receive second treatment of HSV-tk after 6 months.

Who Is Running the Clinical Trial?

The Methodist Hospital Research Institute

Lead Sponsor

Trials

299

Recruited

82,500+

Published Research Related to This Trial

Adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene (tk) showed significant antitumor effects in an oral cancer model in mice, indicating its potential efficacy for treating solid tumors.

The treatment was found to be safe, as no cytopathic effects were observed in distant organs, and there were no significant changes in liver, renal, or bone marrow function after administration, even at high doses of the adenoviral vector.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of in vivo adenovirus-mediated thymidine kinase treatment of oral cancer. Sewell, DA., Li, D., Duan, L., et al.[2019]

High-capacity adenovirus vectors (HC-Ads) carrying the herpes simplex virus type 1-thymidine kinase (TK) gene can induce tumor regression and improve long-term survival in a glioblastoma multiforme model, even when the immune system has pre-existing responses against the adenovirus.

In contrast, first-generation adenovirus vectors (Ad-TK) were ineffective in promoting tumor regression, highlighting the potential of HC-Ads as a more effective gene therapy strategy for treating this aggressive brain cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-capacity adenovirus vector-mediated anti-glioma gene therapy in the presence of systemic antiadenovirus immunity. King, GD., Muhammad, AK., Xiong, W., et al.[2021]

The study developed a retroviral vector that combines two therapeutic genes, HSV-TK and IL-2, which showed higher expression in differentiated thyroid carcinoma cells and led to significant tumor reduction in both in vitro and in vivo models.

Using ganciclovir with the IL-2/HSV-TK combination resulted in complete eradication of anaplastic tumors and over 80% reduction in differentiated thyroid carcinomas, demonstrating that this combined gene therapy approach is more effective than using IL-2 alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase. Barzon, L., Bonaguro, R., Castagliuolo, I., et al.[2019]

Adenovirus-mediated gene therapy using the HSV-tk gene effectively treated brain tumors in a rat model, allowing tumor cells to convert ganciclovir into a toxic form, leading to complete tumor elimination in treated animals.

Rats receiving the ADV-tk gene therapy along with ganciclovir survived significantly longer (up to 120 days) compared to untreated rats, indicating a promising approach for enhancing survival in brain tumor patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated gene therapy of experimental gliomas. Perez-Cruet, MJ., Trask, TW., Chen, SH., et al.[2013]

The ADV-TK gene therapy, combined with ganciclovir (GCV), effectively killed 11 out of 14 types of cultured tumor cells, achieving over 74% killing efficiency, indicating its strong anti-tumor potential.

The treatment's effectiveness was comparable to that of cisplatin, a standard chemotherapy drug, suggesting that ADV-TK could be a promising option for future clinical applications in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Killing effect of adenovirus vector-mediated herpes simplex virus thymidine kinase gene recombinant construct on various cancer cells]. Zhou, JF., Chen, G., Lu, YP., et al.[2015]

The combination of adenoviruses Ad-TK and GCV, along with Ad-Flt3L, showed the highest efficacy in treating glioblastoma (GBM), achieving 70% long-term survival in rats with large tumors, compared to other proapoptotic treatments.

Ad-TK+GCV demonstrated a better safety profile, causing less severe neuropathology than treatments using FasL and TRAIL, making it a promising candidate for a phase I clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. Candolfi, M., Yagiz, K., Foulad, D., et al.[2021]

Adenovirus-mediated transfer of the HSV-tk gene significantly prolonged survival in rats with brain tumors when followed by ganciclovir (GCV) treatment, demonstrating its efficacy as a therapeutic approach.

Both adenovirus and retrovirus-mediated gene transfer of HSV-tk resulted in similar survival benefits, indicating that either method can be effective for treating brain tumors in this model, while other methods without GCV did not lead to tumor cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. Vincent, AJ., Vogels, R., Someren, GV., et al.[2013]

The study evaluated the safety and activity of two adenoviral vectors (Ad-hCMV-TK and Ad-hCMV-Flt3L) in 18 patients with high-grade glioma, showing that the treatment was well-tolerated with no dose-limiting toxicities observed.

The median overall survival for patients was 21.3 months, suggesting that this combination therapy is promising and warrants further investigation in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial. Umemura, Y., Orringer, D., Junck, L., et al.[2023]

In a study involving 72 nude mice with human glioblastoma, combining adenoviral HSV TK gene therapy with radiation therapy significantly prolonged median survival by 5 days without increasing toxic side effects.

The combination treatment also reduced neurological symptoms and delayed the onset of deficits, suggesting a safer and more effective approach for glioblastoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The combination of adenoviral HSV TK gene therapy and radiation is effective in athymic mouse glioblastoma xenografts without increasing toxic side effects. Nestler, U., Wakimoto, H., Siller-Lopez, F., et al.[2019]

HSV tk gene therapy combined with ganciclovir shows promise for treating malignant glioma, with adenovirus vectors leading to better patient outcomes compared to retrovirus vectors, as evidenced by longer survival times (15.0 months vs. 7.4 months).

The therapy was generally safe, with only mild adverse effects such as increased anti-adenovirus antibodies and occasional fever, while no severe adverse events were linked to the gene therapy, supporting the need for further trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. Sandmair, AM., Loimas, S., Puranen, P., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4826211/

Adenovirus-mediated delivery of herpes simplex virus ... Our study demonstrated a notable improvement of PFS-6, PFS and OS in ADV-TK treated group, and the efficacy and safety appear to be comparable to other reported ...

2. cureus.com cureus.com/abstracts/1277-efficacy-of-adenovirus-mediated-delivery-of-herpes-simplex-virus-thymidine-kinase-adv-tk-gene-therapy-combined-with-antiviral-agents-in-giloblastoma-treatment--a-systematic-review-and-meta-analysis

Efficacy Of Adenovirus-mediated Delivery Of Herpes ... Our study demonstrates that Adenovirus-mediated herpes simplex virus thymidine kinase (Adv-tk) gene therapy with antiviral treatment significantly enhances ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26716896/

Adenovirus-mediated delivery of herpes simplex virus ... Our study demonstrated a notable improvement of PFS-6, PFS and OS in ADV-TK treated group, and the efficacy and safety appear to be comparable to other ...

4. link.springer.com link.springer.com/article/10.1023/B:NEON.0000003657.95085.56

Adenovirus/Herpes Simplex-Thymidine Kinase/Ganciclovir ... We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC). Entry ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1525001604013723

AdvHSV-tk gene therapy with intravenous ganciclovir ... It is concluded that AdvHSV-tk gene therapy with GCV is a potential new treatment for operable primary or recurrent high-grade glioma.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/14682378/

Adenovirus/herpes simplex-thymidine kinase/ganciclovir ... We report on a clinical trial of patients with recurrent glioblastoma treated with adenovirus/herpex simplex-thymidine kinase/ganciclovir (ADV/HSV-tk/GC).

7. ir.candeltx.com ir.candeltx.com/news-releases/news-release-details/candel-therapeutics-announces-publication-phase-1b-clinical

Release Details Data published in Neuro-Oncology demonstrate promising safety profile and potential survival benefit when combining CAN-2409 and nivolumab with standard of ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S1525001605010798

Gene Therapy for Malignant Glioma: Current Clinical Status Glioblastoma is an aggressive brain tumor with a dismal prognosis. Gene therapy may offer a new option for the treatment of these patients.