Clinical trial NCT04364178: Viral Specific T-Lymphocytes to Treat Adenovirus or CMV
Official title: Viral Specific T-Lymphocytes by Cytokine Capture System (CCS) to Treat Infection With Adenovirus or Cytomegalovirus After Hematopoietic Cell Transplantation or Solid Organ Transplantation and in Patients With Compromised Immunity
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Adenovirus
Cytomegalovirus Infections
Keywords: Cytokine Capture System
Adenovirus
Cytomegalovirus
Hematopoietic Cell Transplant
Solid Organ Transplant
Immunocompromised
Inborn Error of Immunity
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2020-04-27
Enrollment: 25
Sex: ALL
Minimum age (years): 1
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 and CMV 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 and CMV. 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 or CMV 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.

Eligibility criteria: 1. 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.
2. Male or female, 1 month through 60 years old, inclusive, at the time of informed consent.
3. 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.
4. 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.
5. Negative pregnancy test for females ≥10 years old or who have reached menarche, unless surgically sterilized.
6. Diagnosis of Adenovirus or CMV infection, persistent despite standard therapy.

   A. Adenovirus Infection or Disease:
   1. 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
   2. 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
   3. Intolerance of or contraindication to antiviral medications.

   B. CMV Infection or Disease:
   1. 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
   2. 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
   3. Intolerance of or contraindication to antiviral medications.
7. Donor Eligibility Criteria

   1. 12 years of age or older
   2. Able to understand and consent/assent to the procedure
   3. Required hemoglobin of 11g/dL

Exclusion Criteria:

1. 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).
2. Active acute GVHD grades II-IV.
3. Active severe chronic GVHD.
4. 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.
5. Active and uncontrolled relapse of malignancy.
6. Anticipated initiation of new lymphotoxic therapy within 4 weeks of viral-specific T cell infusion.
7. Patients who are pregnant or lactating.
8. 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.
9. Donor Exclusion Criteria

   1. Patients who are pregnant
   2. Patients who are HIV positive
   3. Uncontrolled infection
   4. Deemed high risk due to pre-existing medical condition

Primary outcomes:
measure: Grade III-IV Acute Graft versus host disease
timeFrame: Day 0 through 90 days after last cellular infusion
measure: CTCAE Grade 4/5 Adverse Events
timeFrame: Day 0 through 30 days from last cellular infusion
Secondary outcomes:
measure: 6-month Survival (continuous)
timeFrame: First cellular infusion to 6 months post first cellular infusion
measure: Viral load by Polymerase Chain Reaction (PCR)
timeFrame: Baseline through study completion, an average of 6 months
measure: Viral load from Respiratory Viral Panel (RVP)
timeFrame: Baseline through study completion, an average of 6 months
measure: Viral load from Bronchoalveolar lavage (BAL)
timeFrame: Baseline through study completion, an average of 6 months
measure: Viral load from Urine
timeFrame: Baseline through study completion, an average of 6 months
measure: Viral load from Stool
timeFrame: Baseline through study completion, an average of 6 months
measure: Viral load from fluid/tissue
timeFrame: Baseline through study completion, an average of 6 months
measure: Clinical response to viral specific infusion
timeFrame: Baseline through study completion, an average of 6 months as clinically indicated
measure: Antiviral Agents
timeFrame: Day 0 through study completion, an average of 6 months
measure: Immune Reconstitution
timeFrame: Baseline through study completion, an average of 6 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Jessie Alexander
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital
state: California
Study officials:
affiliation: Stanford University
name: Jessie Alexander, MD
role: PRINCIPAL_INVESTIGATOR
References: