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

Trial Summary

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.

What data supports the effectiveness of the treatment HLA-matched VSTs for viral infections post stem cell transplant?

Research shows that using virus-specific T cells (VSTs) can effectively restore virus-specific immunity and control viral infections after stem cell transplants, with response rates of 60% to 90% in patients. This approach has been shown to be safe and effective for treating or preventing infections like cytomegalovirus and Epstein-Barr virus, with minimal side effects. ^{1 2 3 4 5}

Is HLA-matched VST treatment safe for humans?

The research does not provide specific safety data for HLA-matched VSTs, but it mentions that HLA mismatches in stem cell transplants can lead to graft-versus-host disease (GVHD), a condition where the donor cells attack the recipient's body. This suggests that careful matching is important to minimize risks. ^{6 7 8 9 10}

How is the treatment HLA-matched VSTs different from other treatments for viral infections after stem cell transplant?

HLA-matched VSTs are unique because they use virus-specific T cells from donors to quickly restore the immune system's ability to fight viral infections after a stem cell transplant, unlike conventional drugs that can be expensive, toxic, and sometimes ineffective. This treatment can be tailored to target multiple viruses and does not cause graft-versus-host disease, making it a promising option when standard therapies fail. ^{1 3 4 5 11}

What is the purpose of this trial?

The purpose of this study is to use VSTs (virus-specific T cells) from a donor that is a partial HLA (human leukocyte antigen) match with the patient to treat viral infections after an allogeneic hematopoietic stem cell transplant (HSCT). These cells may also have value in CAR-T recipients who have received a product that depletes virus specific T cells. The patient must have had a myeloablative or non-myeloablative allogeneic HSCT using either bone marrow, single/double umbilical cord blood, or peripheral blood stem cells (PBSC) or CAR T cell product targeting an antigen expressed on virus specific T cells. After a transplant, while the immune system grows back, the patient is at risk for infection. Some viruses can stay in the body for life and are normally controlled by a healthy immune system, but if the immune system is weakened, like after a transplant, they can cause life threatening infections. He/she must have had an infection with one or more of the following viruses -Epstein Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), Human polyomavirus type I (BKV), and human polyomavirus type II (JCV)- that has persisted or recurred despite standard therapy. In this study, the investigators want to use white blood cells that have been trained to treat viral infections. In an earlier study the investigators showed that treatment with such specially trained T cells has been successful when the cells are made from the transplant donor. However as it takes 1-2 months to make the cells, that approach is not practical for patients who already have an infection. In a subsequent study, the investigators were able to create multivirus-specific T cells (VSTs) from the blood of healthy donors and created a bank of these cells. The investigators then successfully used these banked cells to treat virus infections after a stem cell transplant. In this study the investigators have further modified their production method to decrease the potential side effects and the investigators want to find out if they can use these banked VSTs to fight infections caused by the viruses mentioned above.

Research Team

John Craddock, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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 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]

References

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

T cells for viral infections after allogeneic hematopoietic stem cell transplant. [2021]

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

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

3. England pubmed.ncbi.nlm.nih.gov

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

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

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

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

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

6. Italy 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. [2021]

7. China pubmed.ncbi.nlm.nih.gov

[Role of IFN-γ + 874 genetic polymorphisms in allogeneic hematopoietic stem cell transplantation]. [2013]

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

PRAME-specific Allo-HLA-restricted T cells with potent antitumor reactivity useful for therapeutic T-cell receptor gene transfer. [2023]

9. England 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. [2005]

10. Germany pubmed.ncbi.nlm.nih.gov

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

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

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