R-MVST Cells for Treatment of Viral Infections

NCT ID: NCT05183490

Last Updated: 2024-12-30

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-05-03
• Study Completion Date: 2026-12-31

Brief Summary

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.

Detailed Description

Starting from childhood, majority of healthy humans are exposed to common viruses such as CMV, EBV, BK and related human polyomaviruses and herpes viruses. Under normal circumstances those infections are well controlled by the adaptive immune system, but never eliminated. Instead, they are fairly inactive and produce relatively few consequences or symptoms. However, when T cell mediated immunity is suppressed, those dormant viruses reactivate and can cause a significant end-organ or severe systemic syndrome. This viral reactivation contributes to morbidity and mortality in recipients of allogeneic stem cell transplant (HCT) and solid organ transplants (SOT), and can affect many other patients who receive immunosuppressive therapies or have underlying pathology that affects T cell function, including patients with autoimmune diseases, congenital immunodeficiencies or HIV/AIDS. As a result of a weakened immune response, conventional antiviral prophylaxis or treatment with acyclovir and ganciclovir/foscarnet (for CMV) or rituximab (against EBV) are not always effective.

The main purpose of this study is to test whether giving an experimental cell product can treat the viral infection in patients who have conditions that cause poor function of their immune system, such as infections caused by viruses such as Cytomegalovirus (CMV), Epstein-Barr Virus (EBV), BK virus, or adenovirus. The cell product is called rapidly generated virus specific T cells or R-MVST.

Conditions

Epstein-Barr Virus Infections; Cytomegalovirus Infections; Adenovirus; BK Virus Infection

Keywords

Rapidly generated virus specific T cells (R-MVST); Refractory viral reactivation

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group A: Allogenic Stem Cell Transplant Recipient (SCT)

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.

Group Type: EXPERIMENTAL

Rapidly generated virus specific T (R-MVST) cells

Intervention Type: DRUG

The R-MVST products will be manufactured individually for each patient from a selected donor; it is an anti-viral prophylaxis and treatment of viral reactivation.

SCT dose escalation:

Cohort / R-MVST dose

• (-1A) 0.25x10^6 R-MVST TNC/kg
• (1A) 0.5x10^6 R-MVST TNC/kg
• (2A) 1x10^6 R-MVST TNC/kg

SOT dose escalation:

Cohort / R-MVST dose

• (-1B) 1x10^6 R-MVST TNC/kg
• (1B) 2x10^6 R-MVST TNC/kg
• (2B) 4x10^6 R-MVST TNC/kg

Group B: Solid organ transplant recipients (SOT)

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 Type: EXPERIMENTAL

Rapidly generated virus specific T (R-MVST) cells

Intervention Type: DRUG

The R-MVST products will be manufactured individually for each patient from a selected donor; it is an anti-viral prophylaxis and treatment of viral reactivation.

SCT dose escalation:

Cohort / R-MVST dose

• (-1A) 0.25x10^6 R-MVST TNC/kg
• (1A) 0.5x10^6 R-MVST TNC/kg
• (2A) 1x10^6 R-MVST TNC/kg

SOT dose escalation:

Cohort / R-MVST dose

• (-1B) 1x10^6 R-MVST TNC/kg
• (1B) 2x10^6 R-MVST TNC/kg
• (2B) 4x10^6 R-MVST TNC/kg

Interventions

Rapidly generated virus specific T (R-MVST) cells

The R-MVST products will be manufactured individually for each patient from a selected donor; it is an anti-viral prophylaxis and treatment of viral reactivation.

SCT dose escalation:

Cohort / R-MVST dose

• (-1A) 0.25x10^6 R-MVST TNC/kg
• (1A) 0.5x10^6 R-MVST TNC/kg
• (2A) 1x10^6 R-MVST TNC/kg

SOT dose escalation:

Cohort / R-MVST dose

• (-1B) 1x10^6 R-MVST TNC/kg
• (1B) 2x10^6 R-MVST TNC/kg
• (2B) 4x10^6 R-MVST TNC/kg

Intervention Type: DRUG

Other Intervention Names

R-MVST infusion

Eligibility Criteria

Inclusion Criteria

• Men and women ages 18 years or older of all ethnic groups will be eligible for the treatment
• Patients with history of HCT or SOT who demonstrate evidence of viral reactivation and/or infection manifesting as end-organ or systemic disease due to one or more of the following viruses: EBV, CMV, ADV or BK virus and suboptimal response to the standard of care therapy.
• Recurrent or Multiple Viral Infection. RVI defined as occurrence of more than one episode of reactivation that required intervention or symptomatic disease in recipient of allogeneic HCT that required standard of care treatment. MVI defined as more than one virus reactivating (defined by PCR positivity) or causing symptomatic systemic or end-organ disease. At least one of those viral reactivations required standard of care intervention. No standard of care therapy is defined for ADV and BK. Patients with multiple infections/reactivations will be eligible as long as at least one of those viral infections meet the criterium of "refractory".

Exclusion Criteria

• Patients with other uncontrolled infections, except for CMV, EBV, ADV or BK. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to the day of infusion. For fungal infections, patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to R-MVST infusion. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection
• Patients who receive corticosteroids at ≥ 0.5mg/kg prednisone or equivalent.
• Patients who received anti-thymocyte globulin (ATG, Alemtuzumab (Campath), or other T-Cell immunosupressive monoclonal antibodies in the last 28 days.
• Patients who received methotrexate, or other antimetabolite-type immunosuppressants that are toxic to proliferating T cells in the last 7 days.
• Patients who received extracorporeal photopheresis within the last 28 days.
• Patients who received checkpoint inhibitor agents (e.g., nivolumab, pembrolizumab, ipilimumab) within 3 drug half-lives of the most recent dose to the infusion of R-MVST.
• Received donor lymphocyte infusion in last 28 days.
• Evidence of GVHD ≥ grade 2
• Evidence of biopsy-proven acute rejection in SOT recipients
• Active and uncontrolled relapse of malignancy
• Patients who are pregnant, or breastfeeding.
• Female of childbearing potential, or male with a female partner of childbearing potential, unwilling to use a highly effective method of contraception.
• Uncontrolled intercurrent illness including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients who have received investigational (IND) product within 14 days of infusion of the the R-MVST cells.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Pawel Muranski

Assistant Professor of Medicine and Pathology and Cell Biology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Pawel Muranski, MD

Role: PRINCIPAL_INVESTIGATOR

Assistant Professor of Medicine and Pathology and Cell Biology

Locations

Columbia University Irving Medical Center

New York, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Nurse Navigator

Role: CONTACT

Phone: (212) 342 5162

Email: cancerclinicaltrials@cumc.columbia.edu

Facility Contacts

Pawel Muranski, MD

Role: primary

Pawel Muranski, MD

Role: backup

References

Englund J, Feuchtinger T, Ljungman P. Viral infections in immunocompromised patients. Biol Blood Marrow Transplant. 2011 Jan;17(1 Suppl):S2-5. doi: 10.1016/j.bbmt.2010.11.008. No abstract available.

Reference Type: BACKGROUND

PMID: 21195305 (View on PubMed)

Tanaka Y, Kurosawa S, Tajima K, Tanaka T, Ito R, Inoue Y, Okinaka K, Inamoto Y, Fuji S, Kim SW, Tanosaki R, Yamashita T, Fukuda T. Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016 Apr;51(4):553-9. doi: 10.1038/bmt.2015.330. Epub 2016 Jan 11.

Reference Type: BACKGROUND

PMID: 26752142 (View on PubMed)

Hill JA, Mayer BT, Xie H, Leisenring WM, Huang ML, Stevens-Ayers T, Milano F, Delaney C, Sorror ML, Sandmaier BM, Nichols G, Zerr DM, Jerome KR, Schiffer JT, Boeckh M. The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality. Blood. 2017 Apr 20;129(16):2316-2325. doi: 10.1182/blood-2016-10-748426. Epub 2017 Feb 16.

Reference Type: BACKGROUND

PMID: 28209721 (View on PubMed)

Other Identifiers

AAAS9079

Identifier Type: -

Identifier Source: org_study_id