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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.

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.

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

Rapidly generated virus specific T (R-MVST) cells

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Pawel Muranski, MD

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.

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.

This is a single center, Phase 1, non-randomized open-label dose escalation study in two groups of immunocompromised patients. The recipients of allogeneic HCT who have will be enrolled in Group A, while SOT recipients will be enrolled in Group B. Each group will undergo independent dose escalation.

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. Starting dose proposed for Group B is based on our previous experience with virus-specific cells used for therapy of JC-PML, where multiple infusions of PyVST cells were used at the doses of up to 2x106 TNC/kg. R-MVST cells will target a particular virus (or several viruses), based on the pattern of viral reactivation seen in each patient.

R-MVST Cells for Treatment of Viral Infections

Phase I Study of Adoptive Immunotherapy of Refractory Viral Infection With ex Vivo Expanded Rapidly Generated Virus Specific T (R-MVST) Cells

This is to measure the incidence of toxicity post-infusion. Toxicities to consider include: GI toxicity, renal toxicity, hemorrhagic toxicity, cardiovascular toxicity hypotension, cardiac arrhythmia and left ventricular systolic dysfunction), neurological toxicity (somnolence and seizure), coagulation toxicity, vascular toxicity and pulmonary toxicity.

This is to measure the incidence of GVHD post-infusion. The safety endpoint will be defined as de novo acute GVHD grade IV within 28 days of the last dose of R-MVST, or grades 3-5 infusion related adverse events within 28 days of the last CTL dose, or grades 4-5 non-hematological adverse events within 28 days of the last CTL dose that are not due to the pre-existing infection or the original malignancy or pre-existing co-morbidities as defined by the N a t i o n a l C a n c e r I n s t i t u t e ( NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.

This is to measure the effect of R-MVST infusion on viral load and possible recovery of antiviral immunity post-infusion. Subjects with complete response, partial response and stable disease will be tallied.

If patient has end-organ involvement, the disease will be monitored for the evidence of clinical response. In case of PTLD/EBV lymphoma, the standard Cheson criteria will be applied (Cheson, Pfistner et al. 2007) for adult patients.

This is to measure the effect of R-MVST infusion on viral load and possible recovery of antiviral immunity post-infusion. The percentage of people in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease, such as cancer. The overall survival rate is often stated as a five-year survival rate, which is the percentage of people in a study or treatment group who are alive five years after their diagnosis or the start of treatment. Also called survival rate.

Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in the ANC to \< 500/mm3 for three consecutive measurements on different days, unresponsive to growth factor therapy that persists for at least 14 days in the absence of a known cause such as relapse. Secondary graft failure will be assessed at 28 days post R-MVST infusion in allo-HCT recipients and in recipients of solid organ transplantation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
R-MVST Cells for Treatment of Viral Infections	NCT05183490	Epstein-Barr Vi... Cytomegalovirus... Adenovirus BK Virus Infect...	Rapidly generat...	18 Years -	Columbia University
R-MVST Cells for Treatment of Viral Infections	NCT05183490	Epstein-Barr Vi... Cytomegalovirus... Adenovirus BK Virus Infect...	Rapidly generat...	18 Years -	Columbia University

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