Viral Specific T-Lymphocytes to Treat Adenovirus, CMV and EBV

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this phase I/II study is to evaluate whether partially matched, ≥2/6 HLA-matched, viral specific T cells have efficacy against adenovirus, CMV, and EBV, in subjects who have previously received any type of allogeneic HCT or solid organ transplant (SOT), or have compromised immunity. Reconstitution of anti-viral immunity by donor-derived cytotoxic T lymphocytes has shown promise in preventing and treating infections with adenovirus, CMV, and EBV. However, the weeks taken to prepare patient-specific products, and cost associated with products that may not be used limits their value. In this trial, we will evaluate viral specific T cells generated by gamma capture technology. Eligible patients will include HCT and/or SOT recipients, and/or patients with compromised immunity who have adenovirus, CMV, or EBV infection or refractory viremia that is persistent despite standard therapy. Infusion of the cellular product will be assessed for safety and efficacy.

Detailed Description
-----------------
If a subject shows a partial response, defined as a decrease in viral load of at least 50% from baseline or 50% improvement of clinical signs and symptoms, or no response, they are eligible to receive up to 4 additional cellular infusions from the same donor, at a minimum of 14-day intervals. If the same donor is no longer available, eligible, or appropriate, another donor may be considered for a maximum of 4 total cellular infusions at the discretion of the study PI and treating physician. A subject will not exceed a maximum of 5 total infusions from 2 donors. Subjects are followed for 1 year post initial viral-specific T cell infusion. If subjects receive additional infusion(s), GvHD and adverse events will be followed for an additional 90 days from last infusion. Data may be abstracted from subjects' medical charts for an additional 1 year after most recent viral-specific T cell infusion.

Official Title
-----------------
Viral Specific T-Lymphocytes by Cytokine Capture System (CCS) to Treat Infection With Adenovirus, Cytomegalovirus or Epstein-Barr Virus After Hematopoietic Cell Transplantation or Solid Organ Transplantation and in Patients With Compromised Immunity

Conditions
-----------------
Adenovirus, Cytomegalovirus Infections, Epstein-Barr Virus Infections

Intervention / Treatment
-----------------
* Biological: Adenovirus Specific T- Lymphocytes
* Biological: Cytomegalovirus Specific T-Lymphocytes
* Biological: Epstein-Barr Virus Specific T-Lymphocytes


Participation Criteria
=================
Eligibility Criteria
-----------------
Patient, parent, or legal guardian must have given written informed consent, according to FDA guidelines. For patients ≥ 7 years of age who are developmentally able, assent or affirmation will be obtained, if feasible. Male or female, 1 month through 60 years old, inclusive, at the time of informed consent. Prior allogeneic hematopoietic stem cell transplant (bone marrow, peripheral blood stem cells, single or double cord blood), OR prior solid organ transplant (liver, kidney, lung and/or heart, intestinal, or multivisceral), OR diagnosis of primary immunodeficiency OR current/recent administration of immunosuppressive therapy for cancer or autoimmune disease. Clinical status, at time of consent, amendable to tapering of steroids to less than 1 mg/kg/day prednisone (or equivalent) prior to cellular infusion. Negative pregnancy test for females ≥10 years old or who have reached menarche, unless surgically sterilized. Diagnosis of Adenovirus, CMV, or EBV infection, persistent despite standard therapy. A. Adenovirus Infection or Disease: Active adenovirus infection: (i.e. gastroenteritis, pneumonia, hemorrhagic cystitis, hepatitis, pancreatitis, meningitis) defined as the demonstration of adenovirus by biopsy specimen from affected site(s) (by culture or histology), or the detection of adenovirus by culture, PCR or direct fluorescent antibody stain in fluid in the presence of worsening or persistent clinical or imaging findings despite at least 14 days of appropriate antiviral therapy (i.e. cidofovir, brincidofovir, or other available pharmacological agents) OR Refractory adenoviremia: defined as DNAemia >5000 copies/mL or <1 log decrease after at least 2 weeks of appropriate antiviral therapy (i.e. cidofovir, brincidofovir, or other available pharmacological agents) OR Intolerance of or contraindication to antiviral medications. B. CMV Infection or Disease: Active CMV infection: (i.e. pneumonia, meningitis, retinitis, hepatitis, hemorrhagic cystitis, and/or gastroenteritis) defined as the demonstration of CMV by biopsy specimen from affected site(s) (by culture or histology) or the detection of CMV by culture, PCR or direct fluorescent antibody stain in fluid in the presence of worsening or persistent clinical or imaging findings despite at least 14 days of appropriate antiviral therapy (i.e. Foscarnet, ganciclovir, cidofovir, or other available pharmacological agents) OR Refractory CMV viremia: defined as the continued presence of DNAemia, with ≥2,000 IU/mL or <1 log decrease after at least 14 days of appropriate antiviral therapy (i.e. Foscarnet, ganciclovir, cidofovir, or other available pharmacological agents) OR Intolerance of or contraindication to antiviral medications. C. EBV Infection or Disease: Biopsy proven lymphoma or posttransplant lymphoproliferative disease with EBV genomes detected in tumor cells by immunocytochemistry (i.e. EBER positive) or in situ PCR, OR Clinical or imaging findings consistent with EBV lymphoma and associated elevated EBV viral load in peripheral blood in a patient where biopsy is deemed too high risk, OR Failure of antiviral therapy, as determined by one of the two bullets below after three weeks of anti-CD20 targeted therapy such as Rituximab. i. There was an increase or less than 50% response at sites of lymphoma disease or lymphoproliferation. ii. There was a rise or a fall of less than 50% in EBV viral load in peripheral blood of PTLD patients. Donor Eligibility Criteria 12 years of age or older Able to understand and consent/assent to the procedure Required hemoglobin of 11g/dL Exclusion Criteria: Received ATG or Alemtuzumab within 28 days of viral-specific T cell infusion and a lack of evidence of T cell survival, defined by <10 CD3+ T cells/uL (in unique situations, plasmapheresis may be considered). Active acute GVHD grades II-IV. Active extensive chronic GVHD. Received donor lymphocyte infusion, with the exception of a fraction of an umbilical cord blood, within 21 days of viral-specific T cell infusion. Subjects receiving a fraction of an umbilical cord blood within 21 days of the viral-specific T cell infusion will not be excluded. Active and uncontrolled relapse of malignancy (other than EBV+ post-transplant lymphoproliferative disorder or lymphoma). Anticipated initiation of new lymphotoxic therapy within 4 weeks of viral-specific T cell infusion. Patients who are pregnant or lactating. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks to participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study. Donor Exclusion Criteria Patients who are pregnant Patients who are HIV positive Uncontrolled infection Deemed high risk due to pre-existing medical condition

Ages Eligible for Study
-----------------
Minimum Age: 1 Month
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Viral Specific T-Lymphocytes<br>Peripheral blood mononuclear cells will be collected from the donor and loaded onto our Miltenyi Biotec CliniMACS Prodigy® or CliniMACS® Plus where they will be stimulated in vitro with viral-specific antigen(s). The cells are then immunomagnetically labeled with interferon gamma via the cytokine capture system. By this method, viral specific, gamma-secreting T cells, are captured in a closed, sterile system. | Biological: Adenovirus Specific T- Lymphocytes<br>* Peripheral blood mononuclear cells will be collected from the donor and loaded onto our Miltenyi Biotec CliniMACS Prodigy® or CliniMACS® Plus where they will be stimulated in vitro with Adenovirus viral-specific antigen(s). The cells are then immunomagnetically labeled with interferon gamma via the cytokine capture system, captured and infused.<br>Biological: Cytomegalovirus Specific T-Lymphocytes<br>* Peripheral blood mononuclear cells will be collected from the donor and loaded onto our Miltenyi Biotec CliniMACS Prodigy® or CliniMACS® Plus where they will be stimulated in vitro with Cytomegalovirus viral-specific antigen(s). The cells are then immunomagnetically labeled with interferon gamma via the cytokine capture system, captured and infused.<br>Biological: Epstein-Barr Virus Specific T-Lymphocytes<br>* Peripheral blood mononuclear cells will be collected from the donor and loaded onto our Miltenyi Biotec CliniMACS Prodigy® or CliniMACS® Plus where they will be stimulated in vitro with Epstein-Barr viral-specific antigen(s). The cells are then immunomagnetically labeled with interferon gamma via the cytokine capture system, captured and infused.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade III-IV Acute Graft versus host disease | The number of patients who develop Grade III-IV acute graft versus host disease (GVHD) attributed to the viral specific T cells. | Day 0 through 90 days after last cellular infusion | 
| CTCAE Grade 4/5 Adverse Events | The incidence of patients who develop CTCAE Grade 4/5 Adverse events | Day 0 through 30 days from last cellular infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 1 Year Survival (continuous) | Number of deaths that occurred from treatment | First cellular infusion to 1 year post first cellular infusion | 
| 6-month Survival (dichotomous) | Number of deaths that occurred from treatment | First cellular infusion to 6 months post first cellular infusion | 
| Viral load by Polymerase Chain Reaction (PCR) | The pace at which the viral load is undetectable in whole blood or plasma | Baseline through study completion, an average of 1 year | 
| Viral load from Respiratory Viral Panel (RVP) | The pace at which the viral load is undetectable from nasopharyngeal swab | Baseline through study completion, an average of 1 year | 
| Viral load from Bronchoalveolar lavage (BAL) | The pace at which the viral load is undetectable from bronchial washing | Baseline through study completion, an average of 1 year | 
| Viral load from Urine | The pace at which the viral load is undetectable from urine sample | Baseline through study completion, an average of 1 year | 
| Viral load from Stool | The pace at which the viral load is undetectable from stool sample | Baseline through study completion, an average of 1 year | 
| Viral load from fluid/tissue | The pace at which the viral load is undetectable from other fluid/tissue sample | Baseline through study completion, an average of 1 year | 
| Clinical response to viral specific infusion | By imaging and symptomatology | Baseline through study completion, an average of 1 year as clinically indicated | 
| Antiviral Agents | The introduction of concomitant antiviral medication post infusion, if any | Day 0 through study completion, an average of 1 year | 
| Immune Reconstitution | The pace of systemic immune reconstitution | Baseline through study completion, an average of 1 year | 
| Chronic Graft versus host disease | The number of patients who develop chronic graft versus host disease (GVHD) post first infusion based on Clinical Chronic GvHD Assessment | Baseline through Day 180 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cytokine Capture System, Adenovirus, Cytomegalovirus, Epstein-Barr Virus, Hematopoietic Cell Transplant, Solid Organ Transplant