R-MVST Cells for Viral Infections

Recruiting in Palo Alto (17 mi)

Overseen by Pawel Muranski, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Columbia University

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

Disqualifiers: Uncontrolled infections, GVHD, Malignancy, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The primary objective is to determine the safety and feasibility of administering R-MVST cells to patients with refractory viral reactivation and/or symptomatic disease caused by Epstein Barr Virus (EBV), cytomegalovirus (CMV), adenovirus (ADV) or BK virus. R-MVST cells will be generated on-demand from the closest partially human leukocyte antigen (HLA)-matched (minimum haploidentical) healthy donors or from the original allo-transplant donor if available. The investigator will closely monitor the recipients for potential toxicities including graft-versus-host disease (GVHD) post-infusion. Secondary objectives are to determine the effect of R-MVST infusion on viral load, possible recovery of antiviral immunity post-infusion and for evidence of clinical responses and overall survival. Recipients will be monitored for secondary graft failure at day 28 post R-MVST infusion.

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.

What data supports the effectiveness of the treatment R-MVST Cells for Viral Infections?

Research shows that virus-specific T cells, like those used in R-MVST treatment, have been effective in treating multiple viral infections in patients with weakened immune systems, such as those who have undergone stem cell transplants. In one study, these cells were safe and led to a 94% success rate in reducing viral infections in transplant patients. ^{1 2 3 4 5}

Is the R-MVST cell treatment safe for humans?

Research shows that R-MVST cells, also known as virus-specific T cells, have been safely used in humans, particularly in patients who have received stem cell transplants. Studies report low incidences of side effects and no severe toxicities, indicating that this treatment is generally safe. ^{1 2 3 6 7}

How is the R-MVST cell treatment different from other treatments for viral infections?

The R-MVST cell treatment is unique because it uses rapidly generated virus-specific T cells that can target multiple viruses at once, making it effective for patients with several viral infections. This approach is faster and more versatile than traditional methods, which often require separate preparations for each virus. ^{1 2 3 8 9}

Research Team

Pawel Muranski, MD

Principal Investigator

Assistant Professor of Medicine and Pathology and Cell Biology

Eligibility Criteria

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 am 18 years or older.

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.

Trial Timeline

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

Treatment Details

Interventions

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

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.

Participant Groups

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+

Dr. Katrina Armstrong

Columbia University

Chief Executive Officer

MD from Johns Hopkins University, MS in Epidemiology from Harvard School of Public Health

Dr. Katrina Armstrong

Columbia University

Chief Medical Officer

MD from Harvard Medical School

Findings from Research

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]

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]

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]

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]

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]

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]

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]

References

1. Japan pubmed.ncbi.nlm.nih.gov

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

2. United States 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. [2022]

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

Activity of broad-spectrum T cells as treatment for AdV, EBV, CMV, BKV, and HHV6 infections after HSCT. [2022]

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

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

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

The pipeline of antiviral T-cell therapy: what's in the clinic and undergoing development. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Virus-specific T-cell banks for 'off the shelf' adoptive therapy of refractory infections. [2018]

7. England 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. [2019]

8. Switzerland 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. [2021]

9. United States 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. [2022]