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 tests a new treatment combining gene therapy, an antiviral drug, radiation, and standard cancer drugs for patients with aggressive brain tumors. The gene therapy helps make cancer cells more sensitive to the antiviral drug, while radiation and chemotherapy work to kill or stop the growth of these cells. The gene therapy has been studied for its ability to enhance the effectiveness of treatments for brain tumors.

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 the gene therapy treatment using ADV/HSV-tk generally safe for humans?

In studies involving humans, some patients experienced an increase in anti-adenovirus antibodies and short-term fever, while others had more frequent seizures. No other significant adverse events related to the gene therapy were reported. ^{1 2 3 4 5}

What makes the Gene Therapy + Chemoradiotherapy treatment for glioblastoma unique?

This treatment combines gene therapy with chemoradiotherapy, using a virus to deliver a gene that makes cancer cells more sensitive to a drug, leading to tumor regression and long-term survival even in the presence of immune responses against the virus, which is a novel approach compared to standard treatments. ^{5 6 7 8 9}

What data supports the effectiveness of the treatment ADV/HSV-tk for glioblastoma?

Research shows that using adenovirus vectors to deliver the herpes simplex virus thymidine kinase gene can lead to tumor regression and longer survival in brain cancer models, even when the immune system is active against the virus. This suggests that the treatment could be effective for glioblastoma. ^{3 4 5 7 10}

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

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]

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]

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 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]

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]

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]

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 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]

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]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

High-capacity adenovirus vector-mediated anti-glioma gene therapy in the presence of systemic antiadenovirus immunity. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Safety of in vivo adenovirus-mediated thymidine kinase treatment of oral cancer. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Herpes simplex virus thymidine kinase gene therapy for rat malignant brain tumors. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Release of HMGB1 in response to proapoptotic glioma killing strategies: efficacy and neurotoxicity. [2021]

5. China pubmed.ncbi.nlm.nih.gov

[Killing effect of adenovirus vector-mediated herpes simplex virus thymidine kinase gene recombinant construct on various cancer cells]. [2015]

6. United States pubmed.ncbi.nlm.nih.gov

Thymidine kinase gene therapy for human malignant glioma, using replication-deficient retroviruses or adenoviruses. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Adenovirus-mediated gene therapy of experimental gliomas. [2013]

8. England 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. [2023]

9. United States 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. [2019]

10. England 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. [2019]