Partially HLA-matched virus-specific T-cell therapy for adenovirus, CMV, or EBV in immunocompromised patients

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

This will try partially matched virus-specific T cells to treat adenovirus, CMV, or EBV infections in people whose immune systems are weakened after stem-cell or organ transplants or other immunodeficiencies.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 25 (estimated)
• Ages: 1 Month to 65 Years
• Sex: All
• Sponsor: Stanford University (Academic / other)
• Drugs / interventions: rituximab, Alemtuzumab, prednisone
• Locations: 3 sites (Palo Alto, California and 2 other locations)
• Trial ID: NCT06909110 on ClinicalTrials.gov

What this trial studies

The trial gives virus-specific T cells generated with gamma capture technology that are at least 2/6 HLA-matched to the recipient to try to restore antiviral immunity against adenovirus, CMV, or EBV. Eligible patients include prior allogeneic hematopoietic cell transplant or solid organ transplant recipients and others with compromised immunity who have persistent or refractory viral infection despite standard therapy. Participants may receive an initial infusion and up to four additional infusions (maximum five total) spaced at least 14 days apart, with safety and antiviral response monitored. Subjects are followed for six months after the first infusion, with additional adverse event monitoring after any later infusions.

Who should consider this trial

Good fit: People aged 1 month to 65 years with prior allogeneic hematopoietic cell transplant, prior solid organ transplant, primary immunodeficiency, or recent immunosuppressive therapy who have persistent adenovirus, CMV, or EBV despite standard treatment are ideal candidates.

Not a fit: Patients whose infections are already controlled by standard therapy or who cannot reduce immunosuppression to the required levels for infusion may not receive benefit from this treatment.

Why it matters

Potential benefit: If successful, this approach could restore antiviral immune control and help clear refractory adenovirus, CMV, or EBV infections, reducing illness and the need for prolonged antiviral drugs.

How similar studies have performed: Donor-derived cytotoxic T-lymphocyte therapies have shown promise in prior studies for these viruses, though partially matched, off-the-shelf approaches are less well established.

Eligibility criteria

Patient Inclusion 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 65 years old, inclusive, at the time of informed consent.
3. Prior allogeneic hematopoietic stem cell transplant, AND/OR prior solid organ transplant (liver, kidney, lung and/or heart, intestinal, pancreatic, and/or multivisceral), AND/OR diagnosis of primary immunodeficiency AND/OR current/recent administration of immunosuppressive therapy for cancer or autoimmune disease.
4. If receiving steroids, must be able to taper dose 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 or post-menopausal.
6. Diagnosis of Adenovirus, CMV, or EBV infection, persistent despite standard therapy.

A. Adenovirus Infection or Disease (at minimum, one of the below sub-criteria must be met):

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)
2. Refractory adenoviremia: defined as DNAemia ≥1000 copies/mL or \<1 log decrease after at least 2 weeks of appropriate antiviral therapy (i.e. cidofovir, brincidofovir, or other available pharmacological agents)
3. Intolerance of or contraindication to antiviral medications.

B. CMV Infection or Disease (at minimum, one of the below sub-criteria must be met):

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)
2. Refractory CMV viremia: defined as the continued presence of DNAemia, with ≥1,000 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)
3. Intolerance of or contraindication to antiviral medications.

C. EBV Infection or Disease (at minimum, one of the below sub-criteria must be met):

1. EBV DNAemia ≥1000 IU/mL, persistent despite 2 doses of rituximab,
2. Biopsy proven lymphoma or lymphoproliferative disease with EBV genomes detected in tumor cells by immunocytochemistry (i.e. EBER positive) or in situ PCR,
3. Clinical or imaging findings consistent with EBV lymphoma or lymphoproliferation with current or recent elevated EBV viral load in peripheral blood in a patient where biopsy is deemed too high risk,
4. Failure of antiviral therapy, as determined by one of the two bullets below after two 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.
5. Intolerance or contraindication to rituximab.

Patient Exclusion Criteria:

1. Received ATG or Alemtuzumab within 21 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 planned 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 (other than EBV+ post-transplant lymphoproliferative disorder or lymphoma).
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, or concomitant medications, 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 Inclusion Criteria

1. Age ≥ 12\*
2. Able to understand and sign the consent/assent to the procedure
3. Partial (2/6 or more) HLA match to the recipient
4. A pediatric donor could be selected as a donor only if a suitable adult donor is not available (as attested by the research team) or is ineligible according to FACT requirements. For pediatric donors:

   * Related to the recipient
   * Apheresis does not need a blood prime before the procedure
   * Adequate peripheral venous access
   * Explicit evaluation of the donors' willingness to donate cells, as attested by the research team
   * Must have understanding that they are helping their ill relative, as attested by the research team
   * Will gain emotional/psychological benefit from their ability to help and want to donate for a relative, as attested by the research team
   * Inclusion of minor donors that are not relatives of the recipient will need to be evaluated on a case-by-case basis for the IRB to evaluate the potential benefit to these participants (whether they will receive an emotional and psychological boost from helping the recipient) \*If the only suitable donor is less than 12 years old, a single patient exception to this inclusion criteria will be submitted and approved by the IRB before obtaining the donor's assent and their LAR consent.

Donor Exclusion Criteria

1. Donor is pregnant
2. Donor is HIV positive
3. Donor is positive for hepatitis B and/or hepatitis C
4. Deemed to be a high-risk donor based on responses to donor risk questionnaire
5. Deemed high risk due to preexisting medical condition or abnormal lab results

Where this trial is running

Palo Alto, California and 2 other locations

• Jessie Alexander — Palo Alto, California, United States (Completed)
• Lucile Packard Children's Hospital — Palo Alto, California, United States (Recruiting)
• Lucile Packard Children's Hospital — Palo Alto, California, United States (Recruiting)

Study contacts

• Principal investigator: Jessie Alexander, MD — Stanford University

Conditions Adenovirus; Cytomegalovirus Infections; Epstein-Barr Virus Infections; Cytokine Capture System; Cytomegalovirus; Epstein-Barr Virus; Hematopoietic Cell Transplant; Solid Organ Transplant