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 three groups of immunocompromised patients. The recipients of allogeneic HCT who will be enrolled in Group A, while SOT recipients will be enrolled in Group B and non-transplanted immunocompromised recipients will be enrolled in Group C. Each group will undergo independent dose escalation.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
18
Group A dose escalation schedule: * Cohort (-1A): 0.25x10\^6 R-MVST TNC/kg * Cohort (1A): 0.5x10\^6 R-MVST TNC/kg * Cohort (2A): 1x10\^6 R-MVST TNC/kg Groups B \& C dose escalation schedule: * Cohort (-1B) + (-1C): 1x10\^6 R-MVST TNC/kg * Cohort (1B) + (1C): 2x10\^6 R-MVST TNC/kg * Cohort (2B) + (2C): 4x10\^6 R-MVST TNC/kg
Columbia University Medical Center / New-York Presbyterian
New York, New York, United States
RECRUITINGIncidence of toxicity that leads to safety endpoint
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.
Time frame: Up to 28 days post R-MVST infusion
Incidence of GVHD post-infusion that leads to safety endpoint
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 cytotoxic T-lymphocyte (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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0.
Time frame: Up to 28 days post R-MVST infusion
Percentage of subjects with good response in viral load or end-organ disease improvement
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 post-transplant lymphoproliferative disorder (PTLD)/EBV lymphoma, the standard Cheson criteria will be applied for adult patients.
Time frame: Up to 1 year after the initial R-MVST infusion
Overall survival rate
This is to measure the effect of R-MVST infusion on viral load and possible recovery of antiviral immunity post-infusion. The overall survival rate is defined as 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.
Time frame: Up to 1 year after the initial R-MVST infusion
Incidence of secondary graft failure
Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in the absolute neutrophil count (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.
Time frame: Day 28 post R-MVST infusion
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