VST Therapy for Post-Transplant Viral Infections

(NATS Trial)

Overseen By Fahmida Hoq, MBBS, MS

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's National Research Institute

Must not be taking: ATG, Campath, Basiliximab, others

Disqualifiers: Uncontrolled infections, GVHD, malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6-8 weeks

32 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that steroids be tapered to less than 0.5 mg/kg/day of prednisone or equivalent. Also, you cannot have received certain immunosuppressive drugs or investigational products within 28 days before the infusion.

What data supports the effectiveness of the VST treatment for post-transplant viral infections?

Research shows that virus-specific T cells (VSTs) can quickly restore antiviral immunity after transplantation, helping to control life-threatening viral infections without causing harmful side effects like graft-versus-host disease. This approach has been effective even when traditional treatments fail, making it a promising option for patients with viral infections after transplants. ^{1 2 3 4 5}

Is VST therapy safe for humans?

Virus-specific T cell (VST) therapy has been studied for over two decades and is generally considered safe, with minimal toxicity and low risk of serious side effects. Most adverse effects are mild to moderate and treatable, and no deaths have been attributed to VST therapy in the studies reviewed. ^{1 4 6 7 8}

How is VST therapy different from other treatments for post-transplant viral infections?

VST therapy uses virus-specific T cells to boost the immune system's ability to fight viral infections after a transplant, unlike traditional drugs that can be expensive, toxic, and sometimes ineffective. This approach can quickly restore antiviral immunity without causing harmful side effects like graft-versus-host disease, making it a promising option for difficult-to-treat infections. ^{1 2 3 4 9}

What is the purpose of this trial?

This Phase I dose-escalation trial is designed to evaluate the safety of rapidly generated multivirus-specific T-cell products with antiviral activity against CMV, EBV, adenovirus, HHV6, BK virus, JC virus, and human parainfluenza-3 (HPIV3), derived from eligible HSCT donors. In this trial, we will utilize a rapid generation protocol for broad spectrum multivirus-specific T cells for infusion to recipients of allogeneic hematopoietic stem cell transplant (HSCT), who are at risk of developing EBV, CMV, adenovirus, HHV6, BKV, JCV and/or HPIV3, or with PCR/culture confirmed active infection(s) of EBV, CMV, adenovirus, HHV6, BKV, JCV, and/or HPIV3 that has failed to resolve with at least 14 days of standard antiviral therapy (if available and tolerated). These cells will be derived from HSCT donors, and the study agent will be assessed at each dose for evidence of dose-limiting toxicities (DLT). This study will have two arms: Arm A will include patients who receive prophylactic treatment, and Arm B will include patients who receive VSTs for one or more active infections with targeted viruses. Determination of the study arm will be determined by the patient's clinical status. Study arms will each be analyzed for safety endpoints and secondary endpoints.

Research Team

Michael D Keller, MD

Principal Investigator

Children's National Research Institute

Eligibility Criteria

This trial is for patients who've had a bone marrow or stem cell transplant and are at risk of, or currently have, certain viral infections (like EBV, CMV) that haven't improved after standard treatment. They should be relatively stable with no severe GVHD, uncontrolled cancer relapse, or recent use of other investigational drugs.

Inclusion Criteria

I am able to reduce my steroid use to less than 0.5 mg/kg/day.

I am able to perform most of my daily activities.

Pulse oximetry of > 90% on room air

Exclusion Criteria

I have moderate to severe graft-versus-host disease.

I haven't had cell therapy, except for transplant-related ones, in the last 28 days.

I haven't received specific immune-suppressing drugs in the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Virus Specific T cells (VSTs) for prophylactic and treatment of active viral infection(s) after HSCT

6-8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including incidence of acute GvHD and adverse events

45 days

Long-term Follow-up

Reconstitution of Antiviral Immunity and monitoring of antiviral response

1 year

Treatment Details

Interventions

• Virus Specific T cells (VSTs)

Trial Overview The trial tests Virus Specific T cells (VSTs) from donors to see if they're safe and can prevent or treat viral infections in people who received allogeneic hematopoietic stem cell transplants. It has two parts: one for prevention and another for active infection treatment.

Participant Groups

Group I: Prophylactic and treatment Experimental Treatment 1 Intervention

Virus Specific T cells (VSTs) for prophylactic and treatment of active viral infection(s) after HSCT. 3 different dose levels starting with 1 x 10E7 /m2 (a T cell number more than an order of magnitude lower than that administered at the time of an unmanipulated marrow infusion), followed by 2 x 10E7/m2 and a final dose 5 x 10E7 VSTs/m2

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Findings from Research

In a study involving 28 patients and 32 virus-specific T cell (VST) treatments over 3 years, the average yield of viable VSTs was 1.83 million cells, with a mean purity of 62.9%, indicating a robust method for generating these cells for antiviral therapy.

The research found that the frequency of VSTs in the donor's blood, particularly for cytomegalovirus (CMV), strongly predicts the quantity of VSTs in the final product, emphasizing the importance of careful donor selection in optimizing treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of the best-suited donor for generating virus-specific T cells. Tasnády, S., Karászi, É., Szederjesi, A., et al.[2020]

Adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs) has emerged as a promising immunotherapeutic approach to effectively combat viral infections after hematopoietic stem cell transplantation (HSCT), addressing the limitations of conventional antiviral drugs.

This method not only helps reconstitute antiviral immunity without causing graft-versus-host disease but also shows potential for broader application beyond individual patients and for treating other viral infections outside of HSCT contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reprint of: Virus-Specific T Cells: Broadening Applicability. Barrett, AJ., Prockop, S., Bollard, CM.[2020]

Adoptive transfer of virus-specific cytotoxic T lymphocytes (VSTs) has emerged as a promising immunotherapeutic approach to effectively combat viral infections after hematopoietic stem cell transplantation (HSCT), offering a way to restore antiviral immunity without causing graft-versus-host disease.

This review highlights the potential of VSTs to improve outcomes for patients suffering from life-threatening viral infections post-transplant and discusses strategies to expand their use beyond individual patient products and into other viral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virus-Specific T Cells: Broadening Applicability. Barrett, AJ., Prockop, S., Bollard, CM.[2021]

A single session of high-intensity interval training (HIT) significantly increased the frequency of virus-specific T cells (VSTs) in donors, showing up to a fivefold higher response compared to continuous exercise.

Moderately fit donors had better responses in VST frequency after exercise, suggesting that HIT can enhance the effectiveness of T-cell donations, particularly for less common viral infections like CMV, EBV, and AdV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-intensity interval training in allogeneic adoptive T-cell immunotherapy - a big HIT? Heinemann, NC., Tischer-Zimmermann, S., Wittke, TC., et al.[2021]

Adoptive immunotherapy using virus-specific cytotoxic T cells (VSTs) has significantly advanced over the past 30 years, providing a promising method to restore immunity against viral infections after organ transplants, particularly for common pathogens like cytomegalovirus and Epstein-Barr virus.

Recent improvements in the manufacturing process of pathogen-specific T cells (pSTs) have made it possible to produce these cells more efficiently and even allow for off-the-shelf options, enhancing their availability for treating infections and related malignancies in transplant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond. Papadopoulou, A., Alvanou, M., Karavalakis, G., et al.[2023]

Adoptive immunotherapy using virus-specific T cells (VSTs) has been shown to be a safe and effective treatment for viral infections in patients who have undergone hematopoietic stem cell transplantation (HSCT), with minimal toxicity and a low risk of graft versus host disease.

VSTs have demonstrated efficacy against several viral infections, including cytomegalovirus and Epstein-Barr virus, highlighting their potential as a therapeutic option during the immune deficient period following HSCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Applications of virus-specific T cell therapies post-BMT. Motta, CM., Keller, MD., Bollard, CM.[2023]

The study successfully produced virus-specific T cells (VST) in 100% of cases using the CliniMACS Prodigy® system, demonstrating a feasible and automated method for therapy that could enhance scalability.

In a retrospective analysis of 26 patients with viral diseases post-hematopoietic stem cell transplantation, VST therapy showed a 77% response rate, significantly improving overall survival for responders compared to non-responders (P<0.001), with a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Automated production of specific T cells for treatment of refractory viral infections after allogeneic stem cell transplantation. Heinz, AT., Calkoen, FGJ., Derbich, A., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Identification of the best-suited donor for generating virus-specific T cells. [2020]

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

Reprint of: Virus-Specific T Cells: Broadening Applicability. [2020]

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

Virus-Specific T Cells: Broadening Applicability. [2021]

4. England pubmed.ncbi.nlm.nih.gov

High-intensity interval training in allogeneic adoptive T-cell immunotherapy - a big HIT? [2021]

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

Pathogen-specific T Cells: Targeting Old Enemies and New Invaders in Transplantation and Beyond. [2023]

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

Applications of virus-specific T cell therapies post-BMT. [2023]

7. Italy pubmed.ncbi.nlm.nih.gov

Automated production of specific T cells for treatment of refractory viral infections after allogeneic stem cell transplantation. [2023]

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

Adverse Effects of Virus-Specific T-Cell Therapy: An Integrative Review. [2020]

9. Japan pubmed.ncbi.nlm.nih.gov

[Viral infections after hematopoietic cell transplantation and treatment with virus-specific T-cell therapies]. [2021]