HLA-matched VSTs for Viral Infections Post Stem Cell Transplant

(TETRAVI Trial)

Recruiting at 1 trial location

Overseen By Dustin McFadden

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: ATG, Campath

Disqualifiers: Uncontrolled infections, Acute GVHD, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 6 weeks

47 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to combat viral infections in individuals who have undergone stem cell transplants. It employs special white blood cells, called virus-specific T cells (VSTs), sourced from healthy donors and partially matched to the patient. These cells are trained to target and fight specific viruses that can cause serious issues if the immune system is weak post-transplant. This trial suits those who have had a stem cell transplant and face a challenging viral infection, such as Epstein Barr virus or cytomegalovirus, that hasn't responded to standard treatments. 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.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that patients should not be receiving certain immunosuppressive medications like ATG or Campath within 28 days of screening. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that special immune cells called virus-specific T cells (VSTs) have successfully treated viral infections after stem cell transplants. Patients who received these specially trained cells generally experienced good results, and the treatment is considered safe.

Studies indicate that the side effects of VST therapy are usually mild and manageable. This suggests that while some side effects may occur, they are typically easy to handle. Earlier research demonstrated that both donor-derived and third-party VSTs have been effective in children and adults after a stem cell transplant.

In summary, based on past studies, VSTs appear safe, with only minor and treatable side effects reported. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about HLA-matched VSTs because they offer a personalized and targeted approach to treat viral infections after stem cell transplants. Traditional treatments often rely on broad-spectrum antiviral drugs, which can sometimes have limited efficacy and cause significant side effects. Unlike these standard treatments, HLA-matched VSTs use virus-specific T cells that are partially matched to the patient's immune system, allowing for a more precise attack on the virus. This method not only enhances the body's ability to fight specific viral infections but also reduces the risk of harming healthy cells, potentially leading to fewer side effects and improved outcomes.

What evidence suggests that HLA-matched VSTs might be an effective treatment for viral infections post stem cell transplant?

Research has shown that special immune cells called virus-specific T cells (VSTs) can help fight viral infections after stem cell transplants. In this trial, participants will receive HLA-matched VSTs, which are stored and ready for quick use. Previous studies demonstrated that these stored VSTs effectively control infections from viruses like Epstein Barr virus (EBV), cytomegalovirus (CMV), and adenovirus (AdV) after a transplant. The new method of producing these VSTs aims to reduce side effects while maintaining their effectiveness. Overall, evidence supports that these customized VSTs can help treat challenging viral infections in patients with weakened immune systems. ^{2 6 7 8 9}

Who Is on the Research Team?

John Craddock, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

This trial is for patients who've had a stem cell transplant or CAR-T therapy and are struggling with persistent viral infections like EBV, CMV, adenovirus, or BK virus despite standard treatments. They should have partially HLA-matched T cells available and be able to taper off steroids. Pregnant women must test negative.

Inclusion Criteria

I have a persistent virus infection despite treatment.

Hgb ≥ 7.0 gm/dl

I am taking 1.0 mg/kg/day or less of steroids.

Exclusion Criteria

I need a lot of oxygen to keep my blood oxygen level normal.

I haven't taken any strong immune system suppressing drugs in the last 28 days.

My cancer has returned and is not under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive partially HLA-matched multivirus-specific cytotoxic T-lymphocytes (VSTs) via intravenous injection. Additional doses may be administered based on patient response and availability of donor cells.

6 weeks

Weekly visits for 6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including viral load assessments and potential additional infusions.

1 year

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• HLA-matched VSTs

Trial Overview

The study tests the use of banked multivirus-specific T cells (VSTs) from donors to treat stubborn viral infections in patients post allogeneic hematopoietic stem cell transplant or CAR-T recipients. The VSTs are designed to fight specific viruses that cause severe complications when the immune system is weak.

How Is the Trial Designed?

Group I: HLA-matched VSTs Experimental Treatment 1 Intervention

Partially HLA-matched VSTs will be thawed and given by intravenous injection. Patients will receive 2 x 10\^7 or 4 x 10\^7 partially HLA-matched MVSTs, depending on their body surface area, as a single infusion. In the rare case where insufficient banked cell product is available, a lower number of cells may be infused with agreement of the principal investigator, patient and/or guardian and the treatment team Additional doses may be from the same donor or a different donor based on available cell lines and patient/disease factors. Decision to switch to a different donor can be made by the principal investigator based on factors that include sequential treatment of different viral infections, concerns for immune escape of the targeted virus and/or availability of a better matched or otherwise superior VST line. Additional treatments will only be given following the agreement of the patient, treating physician, and investigator. This process can be repeated as needed.

HLA-matched VSTs is already approved in United States for the following indications:

Approved in United States as VSTs for:

• Epstein Barr virus (EBV) infections
• Cytomegalovirus (CMV) infections
• Adenovirus (AdV) infections
• Human polyomavirus type I (BKV) infections
• Human polyomavirus type II (JCV) infections

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Published Research Related to This Trial

In a study analyzing T-cell subsets from healthy donors, it was found that naïve T cells (identified by CD45RA) are primarily responsible for allogeneic HLA-reactivity, which is linked to graft-versus-host disease in stem-cell transplantation.

Memory T cells showed significantly lower reactivity to allogeneic HLA antigens, suggesting that using memory-depleted T cells could reduce the risk of graft-versus-host disease in HLA-mismatched patients while still allowing for effective anti-leukemia responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alloreactive and leukemia-reactive T cells are preferentially derived from naive precursors in healthy donors: implications for immunotherapy with memory T cells. Distler, E., Bloetz, A., Albrecht, J., et al.[2021]

The study identified high-avidity T cells that specifically target the PRAME antigen on melanoma cells, showing strong potential for antitumor activity without affecting nonmalignant cells, which suggests a promising avenue for targeted cancer therapies.

These PRAME-specific T cells also displayed low reactivity against mature dendritic cells and kidney epithelial cells, indicating a potential for reduced side effects in adoptive T-cell therapy, but further clinical studies are needed to understand the implications of this reactivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRAME-specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer. Amir, AL., van der Steen, DM., van Loenen, MM., et al.[2023]

HLA-identical twins and siblings are the preferred donors for bone marrow transplants (BMT) due to lower risks of graft-versus-host disease (GVHD), while haploidentical donors present increased risks due to more HLA incompatibilities.

Early HLA typing of both the patient and potential donors is crucial in donor selection, and the absence of donor-specific HLA antibodies in the recipient is essential for a successful transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histocompatibility and bone marrow transplantation (BMT). Richter, KV.[2005]

Adoptive transfer of donor-derived virus-specific T cells (VSTs) has shown effectiveness in restoring immunity against viral infections after hematopoietic stem cell transplantation (HSCT), with success rates of 70% to 90% in recipients.

Recent studies have also demonstrated that using closely matched third-party VSTs can provide protection, achieving response rates of 60% to 70%, which is crucial for patients with virus-naïve donors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells for viral infections after allogeneic hematopoietic stem cell transplant. Bollard, CM., Heslop, HE.[2021]

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]

In a study of 80 HLA-matched sibling hematopoietic stem cell transplant (HSCT) pairs, recipients with donors having the IFN-γ + 874 A/A genotype experienced faster neutrophil recovery, averaging 15 days compared to 18 days for those with non-A/A genotypes (P = 0.029).

However, the IFN-γ + 874 A/A genotype in recipients was linked to a higher risk of severe acute graft versus host disease (aGVHD) and cytomegalovirus (CMV) infection, leading to increased 5-year transplant-related mortality (33.7% vs 12.0%, P = 0.050) and decreased event-free survival (58.2% vs 84.0%, P = 0.032).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Role of IFN-γ + 874 genetic polymorphisms in allogeneic hematopoietic stem cell transplantation]. Cai, XJ., Song, AX., Wang, H., et al.[2013]

In a study of 58 patients undergoing nonablative stem cell transplantation (NST) using sibling donors, those with HLA identical (6/6) matches had significantly better median survival (33 months) compared to those with HLA compatible (5/6) matches (8 months).

While there were trends indicating higher rates of acute and chronic graft-versus-host disease (GVHD) in patients with 5/6 matches, the overall outcomes suggest that NST can be safely performed with either type of donor, although HLA identical matches may provide better survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Significance of one human leukocyte antigen mismatch on outcome of nonmyeloablative allogeneic stem cell transplantation from related donors using the Mexican schedule. Ruiz-Argüelles, GJ., López-Martínez, B., Manzano, C., et al.[2005]

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]

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), 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]

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]

Citations

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Outcomes with Third Party Virus Specific T-cells After the Use ...

HLA restriction of a third party VST bank can be determined and annotated using single antigen cell lines. Outcomes for patients who had VST ...

2.

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Here we report on 25 patients who received TP VSTs for the treatment of 26 viral infections with at least one match at an HLA restricted site.

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academic.oup.com/jpids/article/13/Supplement_1/S49/7615748

Virus-Specific T Cells for the Treatment of Systemic Infections ...

Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted . Blood Adv.

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T-cells: Third Party Parity for Viral Infections

Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted. Blood Adv, 5 (17) (2021) ...

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Treatment success will be measured by assessing different parameters including symptoms, quality of life, viral load and T-cell immunity in blood samples.

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Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6750917/

Adverse Effects of Virus-Specific T-Cell Therapy

Studies reviewed indicate that the adverse effects associated with VST therapy are limited and generally treatable.

8.

clinicaltrials.gov

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Study Details | NCT03475212 | Antiviral Cellular Therapy ...

The purpose of this study is to evaluate whether virus-specific T cell lines (VSTs) are safe and can effectively control three viruses (EBV, CMV, ...

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sciencedirect.com

sciencedirect.com/science/article/pii/S2666636723000647

Third-Party and Patient-Specific Donor-Derived Virus ...

Both donor-derived (DD) and third-party (TP) virus-specific T cells (VSTs) have shown efficacy and safety in viral management following HSCT in children and ...