Gene Therapy + Chemoradiotherapy for Glioblastoma

Overseen By Helga M Jones

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: David Baskin MD

Must not be taking: Immunosuppressants, Immunotherapy

Disqualifiers: Liver disease, Alcohol abuse, HIV, others

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

Compensation: Varies

Number of Visits: 10

62 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the safety and effectiveness of a new treatment that combines gene therapy (ADV/HSV-tk), valacyclovir, radiotherapy, and chemotherapy for individuals with recurrent glioblastoma multiforme, an aggressive brain tumor. The treatment involves injecting a gene therapy product during surgery, followed by medication and radiation sessions, with the possibility of repeating the gene therapy after six months. This trial may suit individuals who have undergone surgery and treatment for glioblastoma but whose cancer has returned. Participants should not have multiple tumor sites or tumors affecting the brainstem and must be willing to undergo additional biopsies. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in glioblastoma treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must not have had any cytotoxic chemotherapy, radiotherapy, immunotherapy, or investigational drugs for your brain tumor within 3 weeks of starting the study treatment.

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

Research has shown that the gene therapy treatment, ADV/HSV-tk, has been tested in people with recurring glioblastoma. These studies indicate that the treatment is generally well-tolerated. For example, one study found that patients who received this gene therapy experienced side effects similar to those of other treatments for the same condition, meaning the side effects were not unusual.

Another study on this treatment reported encouraging safety results. While some side effects may occur, these studies suggest that the gene therapy does not cause unexpected or severe reactions in most patients. This indicates a level of safety that makes it worth considering for those interested in joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for glioblastoma rely on a combination of surgery, radiation, and chemotherapy to target cancer cells. But ADV/HSV-tk gene therapy works differently by introducing a virus into the tumor cells during surgery. This virus makes the cells more vulnerable to the antiviral drug valacyclovir, essentially turning the cancer's own machinery against it. Researchers are excited because this method targets the tumor more precisely, potentially reducing damage to healthy brain tissue and improving patient outcomes. Additionally, the ability to administer a second dose of HSV-tk after six months offers a unique opportunity to tackle any remaining or recurring cancer cells.

What evidence suggests that this gene therapy could be effective for glioblastoma?

Research has shown that a gene therapy called ADV/HSV-tk, which participants in this trial will receive, may help treat glioblastoma, a type of brain cancer. Studies have found that this treatment can significantly extend the time patients live without cancer progression and improve overall survival. ADV/HSV-tk uses a virus to deliver a gene into cancer cells, increasing their sensitivity to antiviral drugs and enhancing treatment effectiveness. Data from earlier trials suggest that this approach boosts the effects of standard treatments like chemotherapy and radiotherapy. Overall, this gene therapy has shown potential as a new option for treating recurrent 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 recurrent anaplastic astrocytoma or glioblastoma multiforme, confirmed by biopsy. Participants must have a life expectancy of at least 12 weeks, be recovered from previous treatments, and not have multifocal disease or brainstem involvement. They should use effective birth control and agree to provide biopsies. Those with other active cancers (except certain skin cancers), pregnant or breastfeeding women, and individuals unable to take oral medications are excluded.

Inclusion Criteria

I have a confirmed diagnosis of recurrent anaplastic astrocytoma or glioblastoma without multiple tumor locations or brainstem involvement.

I may have cancer cells in the fluid around my brain and spinal cord.

I have signed and understand the consent form for this study.

Exclusion Criteria

I haven't had chemotherapy, radiation, immunotherapy, or experimental drugs for my brain tumor in the last 3 weeks.

I have no active cancer except for certain skin cancers or treated cancers that have been clear for over 5 years.

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 and radiotherapy over 10 sessions within 2 weeks

2 weeks

10 visits (in-person for radiotherapy)

Chemotherapy

Standard of care chemotherapy is administered concurrent with or after radiotherapy

Varies based on patient status

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

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

What Are the Treatments Tested in This Trial?

Interventions

• ADV/HSV-tk

Trial Overview The study tests the combination of HSV-tk gene therapy with valacyclovir medication, stereotactic body radiotherapy (SBRT), and chemotherapy in patients who have had their glioblastoma return. It aims to evaluate the safety and effectiveness of this approach.

How Is the Trial Designed?

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

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 10 sessions (over 2 weeks) starting within 9 days of surgery. Standard of care/routine chemotherapy will be started concurrent or after completion of the radiotherapy dependent on patient status based on best clinical judgment. Patient can receive second treatment of HSV-tk after 6 months

Who Is Running the Clinical Trial?

David Baskin MD

Lead Sponsor

Trials

1

Recruited

60+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Published Research Related to This Trial

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 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 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]

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]

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 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 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]

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]

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]

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.