Gene Therapy + Radiotherapy for Brain Tumor

Overseen By Nyati Shyam, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Henry Ford Health System

Must not be taking: Immunosuppressants

Disqualifiers: Acute infection, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 4

Duration: 30 days

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose for a new gene therapy combined with radiotherapy to treat recurring high-grade astrocytoma, an aggressive brain tumor. The treatment involves injecting a modified virus (Ad5-yCD/mutTKSR39rep-ADP adenovirus) directly into the tumor to kill cancer cells, followed by targeted radiation therapy. Individuals previously diagnosed with high-grade astrocytoma, whose tumors have returned, and who can undergo surgery, may be suitable candidates for this study. 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 protocol does not specify if you need to stop taking your current medications. However, you must have recovered from previous treatments and cannot be on immunosuppressive therapy, except for corticosteroids.

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

Research shows that the Ad5-yCD/mutTKSR39rep-ADP adenovirus in this trial is part of a new cancer treatment called oncolytic viruses. These viruses target and destroy cancer cells while sparing healthy ones. Previous studies have shown promising results, with the virus effectively controlling tumor growth in animals. However, detailed safety information in humans is still being collected, as this treatment is in the early testing stages.

For the fractionated stereotactic radiosurgery (fSRS) component, research indicates it is a safe and effective method for treating brain tumors. It uses high-dose radiation focused on the tumor to damage cancer cells while minimizing harm to nearby healthy tissue. Since fSRS is already a common treatment for brain tumors, its safety is well-known and generally considered favorable.

Overall, while researchers continue to study the adenovirus treatment for safety in humans, existing data shows the fSRS component is well-tolerated. Participants in the trial should discuss potential risks and benefits with the research team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for brain tumors, which often include surgery, chemotherapy, and traditional radiation therapy, this new approach combines gene therapy with Fractionated Stereotactic Radiosurgery (fSRS). The gene therapy uses an adenovirus called Ad5-yCD/mutTKSR39rep-ADP, which is directly injected into the tumor. This virus has been engineered to selectively target and destroy cancer cells. By combining this with precise radiation therapy like fSRS, researchers hope to enhance the treatment's effectiveness while minimizing damage to surrounding healthy brain tissue. This targeted approach is why researchers are excited, as it could potentially lead to better outcomes with fewer side effects.

What evidence suggests that this trial's treatments could be effective for brain tumors?

Research has shown that the Ad5-yCD/mutTKSR39rep-ADP adenovirus, which participants in this trial may receive, can help control tumors. This treatment uses a specially designed virus to target cancer cells and has proven more effective in controlling tumors than earlier treatments. Studies also indicate it can trigger the body's immune system to fight the tumors. Fractionated Stereotactic Radiosurgery (fSRS), also part of this trial, is a precise radiation therapy that targets tumor cells while protecting healthy brain tissue. It effectively controls tumors with few side effects. When used together in this trial, both treatments have effectively managed tumors, offering potential benefits for patients with recurring high-grade astrocytomas. ^{1 2 3 4 6}

Who Is on the Research Team?

Tobias Walbert, MD, PhD, MPH

Principal Investigator

Henry Ford Health System

Are You a Good Fit for This Trial?

Adults with recurrent high-grade astrocytoma eligible for tumor resection, not previously treated with certain gene/immunotherapies or implants. Must have good organ function, no immune disorders, and agree to birth control. Excludes those with serious illnesses that could interfere with the trial, pregnant/lactating women, allergy to protocol products, impaired immunity, inability to undergo MRI, acute infections or liver disease.

Inclusion Criteria

I can care for myself but may need occasional help.

Hemoglobin > 10.0 g/dL

It has been over 4 weeks since my last non-nitrosourea chemotherapy.

Exclusion Criteria

Pregnant or lactating females

My immune system is weak and I easily get serious viral infections.

I am not on immunosuppressive therapy, except for corticosteroids.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Surgery and Adenovirus Injection

Patients undergo repeat surgery for tumor resection followed by intratumoral injection of modified oncolytic adenovirus

1 day

1 visit (in-person)

Treatment

Participants receive fractionated stereotactic radiosurgery combined with oral 5-fluorocytosine and valganciclovir prodrug therapy

30 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days

Multiple visits (in-person and virtual) at days 3, 7, 14, 21, 30, and 90

What Are the Treatments Tested in This Trial?

Interventions

• Ad5-yCD/mutTKSR39rep-ADP adenovirus
• Fractionated Stereotactic Radiosurgery (fSRS)

Trial Overview The study tests a maximum tolerated dose of Ad5-yCD/mutTKSR39rep-ADP adenovirus combined with fractionated stereotactic radiosurgery in patients undergoing surgery for recurrent high-grade astrocytoma. It's a Phase I trial focused on safety and dosage levels.

How Is the Trial Designed?

Group I: Ad5-yCD/mutTKSR39rep-ADP adenovirus and fSRS Arm Experimental Treatment 1 Intervention

Subjects will receive a single intratumoral injection of the Ad5-yCD/mutTKSR39rep-ADP adenovirus at one of three dose levels beginning at 1 x 1011 vp and escalating in half-log (3-fold) increments to 1 x 1012 vp, along with the same dose of fractionated stereotactic radiosurgery until unacceptable toxicity, disease progression, or withdrawal of consent.

Who Is Running the Clinical Trial?

Henry Ford Health System

Lead Sponsor

Trials

334

Recruited

2,197,000+

Published Research Related to This Trial

Transducing human U87 MG glioma cells with the adenovirus-expressing mutant HSV-TK75 (AdCMV-TK75) significantly increases their sensitivity to the antiviral drug acyclovir (ACV), enhancing radiosensitization compared to wild-type HSV-TK or control viruses.

In vivo studies showed that U87 MG xenografts treated with AdCMV-TK75 and ACV exhibited dramatic radiosensitization, especially when ACV was administered concurrently with radiation therapy, leading to complete tumor growth inhibition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization of human glioma cells in vitro and in vivo with acyclovir and mutant HSV-TK75 expressed from adenovirus. Rosenberg, E., Hawkins, W., Holmes, M., et al.[2019]

The antiviral drug BVdUrd can enhance the effectiveness of radiation therapy in human glioma cells that have been genetically modified to express the HSV-tk thymidine kinase gene, showing a sensitization enhancement ratio of 1.9.

This study suggests that combining BVdUrd with radiation therapy could improve outcomes in treating brain tumors, leveraging the drug's ability to interfere with DNA integrity to increase radiation sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective enhancement by an antiviral agent of the radiation-induced cell killing of human glioma cells transduced with HSV-tk gene. Kim, JH., Kim, SH., Brown, SL., et al.[2014]

The FGR adenovirus, designed with a double-suicide gene therapy approach, effectively targets and destroys tumor cells lacking functional p53 while showing no significant toxicity to normal human cells, indicating a safer treatment option.

Combining the FGR virus with suicide gene systems enhances the tumor-specific effects and sensitizes cancer cells to radiation, suggesting that this three-pronged strategy could significantly improve cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Freytag, SO., Rogulski, KR., Paielli, DL., et al.[2020]

The Phase I study involving 16 patients tested a novel adenovirus-mediated gene therapy (Ad5-CD/TKrep) for treating local recurrence of prostate cancer, showing it can be safely administered with no dose-limiting toxicities and mostly mild adverse events.

The therapy demonstrated biological activity, with 44% of patients experiencing a significant decrease in prostate-specific antigen levels, indicating potential effectiveness in targeting cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Freytag, SO., Khil, M., Stricker, H., et al.[2021]

The second-generation adenovirus, Ad5-yCD/mutTK(SR39)rep-ADP, shows improved tumor cell killing and better tumor control in preclinical models compared to the first-generation version, indicating enhanced efficacy for cancer treatment.

Safety assessments reveal that Ad5-yCD/mutTK(SR39)rep-ADP does not significantly increase toxicity compared to the earlier adenovirus, which has already been proven safe in human trials, supporting its potential for clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Second-generation replication-competent oncolytic adenovirus armed with improved suicide genes and ADP gene demonstrates greater efficacy without increased toxicity. Barton, KN., Paielli, D., Zhang, Y., et al.[2021]

The combination of adenoviral-directed cytosine deaminase (CD) gene therapy with radiation therapy significantly enhanced tumor regression in human cancer xenografts, with larger tumors showing a reduction to 11% of their original volume after treatment.

Smaller tumors treated with the same combined approach not only showed significant regression but also continued to shrink over time, with 43% of these tumors cured by day 26, indicating that this gene therapy could improve local tumor control and potentially increase survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virally directed cytosine deaminase/5-fluorocytosine gene therapy enhances radiation response in human cancer xenografts. Hanna, NN., Mauceri, HJ., Wayne, JD., et al.[2013]

The replication-competent adenovirus Ad5-CD/TKrep showed significant antitumor activity against cervical carcinoma in vivo, especially when combined with double prodrug therapy (5-FC + GCV) and radiation therapy.

This trimodal treatment approach led to remarkable tumor regression and a 100% cure rate, highlighting its potential for future clinical trials in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double suicide gene therapy augments the antitumor activity of a replication-competent lytic adenovirus through enhanced cytotoxicity and radiosensitization. Rogulski, KR., Wing, MS., Paielli, DL., et al.[2020]

Human adenoid cystic carcinoma (ACC-2) cells modified with a CD/HSV-TK fusion gene showed increased sensitivity to radiation when treated with prodrugs 5-fluorocytosine and ganciclovir, suggesting enhanced therapeutic efficacy.

The study found that ACC-2/CD-TK cells had lower capacity for damage repair and greater radiosensitivity compared to unmodified ACC-2 cells, indicating that combining radiation with CD-TK gene therapy could significantly improve treatment outcomes for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiosensitization and anti-tumour effects of cytosine deaminase and thymidine kinase fusion suicide gene in human adenoid cystic carcinoma cells. Huang, SY., Zhang, DS., Han, JQ., et al.[2017]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10088621/

Oncolytic virus-based suicide gene therapy for cancer ... Henry Ford Health investigators developed the Ad5-yCD/mutTKSR39rep-ADP oncolytic adenovirus, which was a second-generation replication competent ...

2. cell.com cell.com/molecular-therapy-family/molecular-therapy/pdf/S1525-0016(05)01643-6.pdf

Second-Generation Replication-Competent Oncolytic ... We made two improvements in the parental Ad5-CD/. TKrep adenovirus, generating the second-generation adenovirus, Ad5-yCD/mutTKSR39rep-ADP. We ...

3. researchgate.net researchgate.net/figure/Comparison-of-in-vivo-efficacy-of-Ad5-CD-TKrep-versus-Ad5-yCD-mutTK-SR39-rep-ADP-LNCaP_fig5_7478767

Comparison of in vivo efficacy of Ad5-CD/TKrep versus ... Ad5-yCD/mutTK SR39 rep- ADP resulted in significantly greater tumor control than Ad5-CD/TKrep both in the absence and in the presence of prodrugs (Fig. 4). In ...

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/97/NCT02555397/Prot_SAP_000.pdf

Phase 1 Locally Recurrent Prostate Cancer Gene Therapy ... Both the yCD and mutant HSV-1 TKSR39 genes have better catalytic properties than the bCD and wild-type HSV-1 TK genes contained in Ad5-CD/TKrep (46, 47). ADP ...

5. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.953410/full

Current clinical landscape of oncolytic viruses as novel ... Further, Ad5-yCD/mutTKSR39rep-hIL12 treatment improved induction of antitumor immune response through expression of hIL12, as evidenced by activation of NKs and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7697649/

Oncolytic Adenovirus in Cancer Immunotherapy - PMC Oncolytic adenoviruses are engineered to selectively replicate in and destroy cancer tissue. Moreover, these viruses are promising tools to restore antitumor ...