R-MVST Cells for Viral Infections

Overseen By Pawel Muranski, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

Must not be taking: Corticosteroids, Antimetabolites, Checkpoint inhibitors, 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: 1

Duration: 28 days per dose

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment using Rapidly generated virus-specific T (R-MVST) cells to manage stubborn viral infections like EBV, CMV, ADV, and BK virus in individuals who have undergone a stem cell or organ transplant. The goal is to determine if these specially crafted cells can safely reduce viral loads and enhance patients' immunity and overall health. Suitable candidates include those with a history of transplant who experience recurring or multiple viral infections unresponsive 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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but certain medications like corticosteroids at high doses, specific immunosuppressants, and investigational products must not be taken close to the infusion. It's best to discuss your current medications with the trial team.

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

Research has shown that virus-specific T-cell (VST) therapy, such as R-MVST cells, has been studied for treating difficult viral infections. These studies indicate that VST therapy is generally safe for humans, having been used for over 20 years to target hard-to-treat infections. Reports suggest that these treatments are usually well-tolerated, though side effects can occur. One study found that VST therapy can help manage infections like Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenovirus (ADV) without causing major problems in most cases.

However, some side effects can occur. Graft-versus-host disease (GVHD) may develop when the donated cells attack the recipient's body, a risk more common in individuals who have had stem cell transplants. The study notes that the risk of GVHD is lower in those who have had solid organ transplants because the infused cells are less likely to remain in the body for a long time.

In summary, while R-MVST cells have shown promise and are usually safe, it is important to be aware of potential risks like GVHD, especially for those who have had a stem cell transplant. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about using Rapidly generated virus specific T (R-MVST) cells because they offer a promising new approach to fighting viral infections in transplant recipients. Unlike standard antiviral medications that target the virus directly, R-MVST cells are engineered to enhance the body's immune response by specifically targeting and destroying virus-infected cells. For patients who have undergone stem cell transplants (Group A), these donor-derived cells are designed to persist longer, potentially reducing the risk of viral reactivation. Meanwhile, for solid organ transplant recipients (Group B), the higher doses of R-MVST cells are expected to offer a robust antiviral response without the long-term complications often seen with existing treatments. This targeted and adaptable approach could lead to faster and more effective management of viral infections in these vulnerable populations.

What evidence suggests that R-MVST cells might be an effective treatment for viral infections?

Research has shown that quickly produced virus-specific T cells, known as R-MVST cells, can help manage viral infections in people with weakened immune systems. In this trial, participants will be divided into two groups: Group A, consisting of allogenic stem cell transplant recipients, and Group B, consisting of solid organ transplant recipients. These cells are specially designed to find and fight viruses like Epstein Barr Virus (EBV), cytomegalovirus (CMV), adenovirus (ADV), and BK virus. Studies have demonstrated that these T cells can rapidly restore the body's ability to combat these viruses. Patients who received similar T cell treatments experienced a decrease in the amount of virus in their bodies. This method shows promise for people with viral infections that do not respond to standard treatments. ^{4 5 6 7 8}

Who Is on the Research Team?

Pawel Muranski, MD

Principal Investigator

Assistant Professor of Medicine and Pathology and Cell Biology

Are You a Good Fit for This Trial?

This trial is for adults who've had a transplant and are struggling with tough-to-treat viral infections like EBV, CMV, ADV, or BK virus. They should have tried standard treatments without enough success. It's not open to people under 18 or those with conditions that don't match the study's focus.

Inclusion Criteria

I had a transplant and now have a virus affecting my body because standard treatments didn't work well.

I have had multiple or recurring viral infections after a bone marrow transplant.

I'm sorry, but that is not a complete criterion. Please provide more information about the criterion to enable me to rewrite it.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of R-MVST Cells, followed by monitoring for toxicity and GVHD for 28 days. Up to two additional doses may be administered, with a minimum of 28 days apart if safety is established.

28 days per dose

1 visit per dose (in-person)

Follow-up

Participants are monitored for virological and clinical responses, as well as overall survival, for up to 1 year after the initial R-MVST infusion.

1 year

Safety Monitoring

Participants are monitored for incidence of GVHD and other toxicities post-infusion, with a focus on safety endpoints within 28 days of the last dose.

28 days post each infusion

What Are the Treatments Tested in This Trial?

Interventions

• Rapidly generated virus specific T (R-MVST) cells

Trial Overview

The trial tests R-MVST cells made from donors' immune cells matched to patients at least by half (haploidentical) or from the original donor of their transplant. The goal is to see if these cells can safely fight off stubborn viruses in patients where usual treatments haven't worked well.

How Is the Trial Designed?

Group I: Group B: Solid organ transplant recipients (SOT) Experimental Treatment 1 Intervention

In SOT recipients, the study will use higher doses of R-MVST cells, as the infused anti-viral T cells are less likely to persist long-term and cause GVHD, based on the safety profile of PyVST cells used for therapy of PML in non-HCT subjects. Subjects will receive a single dose of R-MVST Cells, and followed for toxicity and GVHD for 28 days days after infusion. Up to two additional doses may be administered, minimum of 28 days apart if cohort safety is established and reinfusion criteria are met. A new 28-day safety-monitoring period will ensue for each additional infusion. Subjects will be followed for possible virological and clinical responses for up to 1 year after the initial R-MVST infusion.

Group II: Group A: Allogenic Stem Cell Transplant Recipient (SCT) Experimental Treatment 1 Intervention

Dose levels selected for Group A are based on previous experience with VST cells in HCT recipients and are lower than in Group B (SOT recipients), as donor-derived R-MVST cells are more likely to persist in recipients of HCT from the same donors. Thus, there is theoretically a higher risk for development of GVHD in this subset of patients. Each group will undergo independent dose escalation. Subjects will receive a single dose of R-MVST Cells, and followed for toxicity and GVHD for 28 days days after infusion. Up to two additional doses may be administered, minimum of 28 days apart if cohort safety is established and reinfusion criteria are met. A new 28-day safety-monitoring period will ensue for each additional infusion. Subjects will be followed for possible virological and clinical responses for up to 1 year after the initial R-MVST infusion.

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Published Research Related to This Trial

Virus-specific T cells can effectively target multiple pathogens in patients who have undergone hematopoietic stem cell transplantation, showing promise against viruses like cytomegalovirus and Epstein-Barr Virus.

The potential to target additional pathogens such as BK virus, JC virus, and Zika virus suggests that this therapy could be expanded to improve patient outcomes, especially with the development of patient-specific and third-party T cell products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pipeline of antiviral T-cell therapy: what's in the clinic and undergoing development. Fatic, A., Zhang, N., Keller, MD., et al.[2022]

A new method for generating virus-specific T cells (VSTs) using peripheral blood mononuclear cells (PBMCs) in serum-free medium allows for the targeting of multiple viruses, including CMV and EBV, without the need for complex preparation of antigen-presenting cells.

This simplified approach not only matches the effectiveness of traditional methods but also reduces costs and variability, making it more suitable for clinical use, especially for immunocompromised patients like those receiving hematopoietic stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of multivirus-specific T cells by a single stimulation of peripheral blood mononuclear cells with a peptide mixture using serum-free medium. Nishiyama-Fujita, Y., Kawana-Tachikawa, AI., Ono, T., et al.[2019]

In a study involving 25 patients who underwent related-donor transplantation, the direct isolation and administration of cytomegalovirus-specific T cells successfully restored antiviral immunity, demonstrating feasibility and effectiveness in a clinical setting.

The infused T cells expanded rapidly in the patients, predominantly consisting of CD4(+) and CD8(+) effector-memory cells, and provided protection against reinfection in most cases, highlighting their potential for broader application in cellular therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Directly selected cytomegalovirus-reactive donor T cells confer rapid and safe systemic reconstitution of virus-specific immunity following stem cell transplantation. Peggs, KS., Thomson, K., Samuel, E., et al.[2022]

Adoptive immunotherapy using virus-specific T cells from transplant donors has shown a promising disease response rate of 50-76% in treating drug-refractory EBV+ lymphomas and infections like CMV and adenovirus, with low toxicity and graft-versus-host disease (GVHD) incidences.

The review highlights the importance of the characteristics of both the viral pathogens and the T cells used, as well as the host's condition, in determining the success of the treatment, suggesting that in vitro culture can enhance the effectiveness of T cells by expanding those that target common viral epitopes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Virus-specific T-cell banks for 'off the shelf' adoptive therapy of refractory infections. O'Reilly, RJ., Prockop, S., Hasan, AN., et al.[2018]

Hematopoietic stem cell transplant (SCT) recipients experience significant immunosuppression, making them vulnerable to viral infections like CMV and EBV, but a competent immune response with viral-specific T cells can reduce infection rates.

Recent advancements in multimer technology and flow cytometry allow for the direct identification and isolation of antigen-specific T cells without lengthy culture processes, paving the way for potential adoptive immunotherapy to enhance immune recovery in SCT patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Viral-specific adoptive immunotherapy after allo-SCT: the role of multimer-based selection strategies. Ramírez, N., Olavarría, E.[2013]

Patients receiving hematopoietic stem cell transplants are at a high risk for viral infections like cytomegalovirus and EB virus due to severe immunosuppression, which can lead to significant health complications.

Recent advancements in generating virus-specific T cells, such as using peptide-HLA multimers and third-party donor banks, have improved the feasibility and speed of T-cell therapy, making it a promising approach for treating viral infections in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy using T cells for treating viral infections]. Takahashi, S.[2019]

The study demonstrated the successful generation of virus-specific T cells (VSTs) that target 12 antigens from five different viruses, showing promise for treating infections in immunocompromised patients.

In a clinical trial involving 11 allogeneic transplant recipients, the VSTs were safe and resulted in a remarkable 94% response rate in managing active viral infections, with effects sustained over the long term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. Papadopoulou, A., Gerdemann, U., Katari, UL., et al.[2022]

SARS-CoV-2-exposed blood donations contain memory T cells that can recognize key viral antigens, allowing for the isolation and expansion of virus-specific T cells for therapy.

Using a GMP-compliant process, these T cells can be rapidly expanded to produce between 10 billion to 100 billion cells in just 21 days, enabling the potential for multiple therapeutic doses for COVID-19 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid GMP-Compliant Expansion of SARS-CoV-2-Specific T Cells From Convalescent Donors for Use as an Allogeneic Cell Therapy for COVID-19. Cooper, RS., Fraser, AR., Smith, L., et al.[2021]

A bank of 32 virus-specific T cell lines was successfully used to treat 50 patients with severe viral infections after stem cell transplants, resulting in a 74% overall response rate within 6 weeks, demonstrating the efficacy of this approach.

The treatment was safe, with no immediate infusion-related adverse events and only 2 cases of de novo graft-versus-host disease, indicating that using banked T cell lines can be a viable option for rapid antiviral therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Leen, AM., Bollard, CM., Mendizabal, AM., et al.[2022]

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