A Dose-Escalation Study Evaluating Safety and Tolerability of Viral-Specific T Cells Against CMV in Adult Solid Organ Transplant Recipients

This study measures the tolerability of viral-specific T cells against Cytomegalovirus (CMV) in adult solid organ transplant (SOT) recipients. Participants are expected to be on study for 52 +/- 3 weeks.

Viral infections, or their reactivation in the immunocompromised host, remain serious complications that adversely affect outcomes of transplantation. These infections may be refractory to pharmacologic treatment and result in increased morbidity and mortality after transplantation. Furthermore, the available pharmacologic therapies can result in severe toxicities.

Once an infection occurs, adequate immune reconstitution is decisive for recovery from viral disease after solid organ transplantation. The present trial will consist of the treatment of solid organ transplant recipients diagnosed with severe CMV infection when standard antiviral therapy is ineffective (disease progression on therapy, decline in viral load less than 10-fold in 2 weeks, known drug resistance), or toxic (end-organ damage), with virus-specific T cells using the CliniMACS® Prodigy System. These are the patients with the greatest unmet need and greatest risk or morbidity and allograft loss due to CMV infection. CMV-specific T cells will be isolated from donor leukapheresis products using the CliniMACS® Prodigy. Prior studies on transfer of CMV-specific T cells have been shown to be safe and efficacious in the treatment of CMV infections.

The primary objective of this Phase I trial is to evaluate the safety and tolerability of CMV-specific T-cell transfer in adult patients suffering from CMV infections following solid organ transplantation using a dose escalation design. The incubation with viral antigens (MACS GMP PepTivator) allows the enrichment of CMV-specific CD4+(Cluster of Differentiation 4) and CD8+(Cluster of Differentiation 8) T cells. Increasing evidence of the safety and efficacy of CMV-specific T-cell is available. Furthermore, the safety and efficacy of the specific manufacturing approach using the fully automated protocol of the ClinMACS® Prodigy for the isolation of CMV-specific T cells against CMV has been described and demonstrated that these cells retain their biological properties.

Eligibility Criteria:
Inclusion Criteria:

1. Adult (age ≥ 18 and ≤75) patients suffering from CMV reactivation/infections following solid organ transplantation (e.g., liver, pancreas, lung, heart, and multi-solid organ)

   * CMV reactivation/viremia defined as positive (\>250 copies/mL) CMV qPCR(quantitative polymerase chain reaction) AND/OR
   * Presence of symptoms secondary to CMV infection or evidence of invasive CMV infection (e.g. pneumonitis, colitis)

   AND ONE OF THE FOLLOWING CRITERIA:
   * Absence of an improvement of viral load after ≥ 14 days of standard antiviral therapy with ganciclovir, valganciclovir or foscarnet (decrease by at least 1 log, i.e. 10-fold), or
   * New, persistent and/or worsening CMV-related symptoms, signs and/or markers of end organ compromise while on anti-viral therapy with medications such as ganciclovir, acyclovir, valganciclovir, foscarnet, cidofovir, IVIG(Intravenous immunoglobulin), and/or letermovir, or
   * Have contraindications or experience adverse effects of anti-viral therapy with medications such as ganciclovir, acyclovir, valganciclovir, foscarnet, cidofovir, IVIG, and/or letermovir, or
   * Known resistance to the anti-viral medications ganciclovir, foscarnet and/or cidofovir based on molecular testing
2. Availability of eligible donor
3. Written informed consent given by patient

Exclusion Criteria:

1. Patient with acute rejection of allograft at time of T-cell transfer
2. Patient receiving steroids (\>0.5 mg/kg body weight (BW) prednisone equivalent) at the time of T-cell transfer
3. Patient treated with Thymoglobulin (ATG), Alemtuzumab or T-cell immunosuppressive monoclonal antibodies within 28 days
4. Patients with CMV retinitis
5. Concomitant enrollment in another clinical trial interfering with endpoints of this study
6. Any medical condition which could compromise participation in the study according to the investigator's assessment
7. Known HIV infection
8. Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control during study treatment Note: Women of childbearing potential must have a negative serum pregnancy test at study entry.
9. Patients unwilling or unable to comply with the protocol or unable to give informed consent

Donor Eligibility

Donor selection priority: The original donor will be the first choice as the source of T cells. If donation from the original organ donor is not possible (e.g., donor is unavailable or ineligible), then an alternative related donor will be selected, with preference for those who have full HLA matching in 6/6 loci over those with partial HLA matching (≥ 2/6 HLA loci). See Appendix 1 for patient and donor screening procedures.

1. ≥ 18 years old
2. Available and capable of undergoing a single standard 2 blood volume leukapheresis or donation of one unit of whole blood.
3. If the original transplant donor is not eligible, then an eligible fully matched or eligible partially matched family member will be used as the donor.
4. Related donors must be at least partially HLA compatible, matching with recipient in at least 2/6 HLA loci (HLA-A, HLA-B and HLA-DRB1 will be considered for this).
5. Donors must be CMV IgG seropositive.
6. Donors must show CMV T-cell activation after incubation with MACS GMP PepTivator Peptide Pools of CMV pp65 before undergoing leukapheresis.
7. Donor must meet the criteria for donor selection defined in the UWHC Hematopoietic Stem Cell Transplant Program SOP and FACT standards, which comply with 21 CFR 1271, subpart C.
8. Donor must provide written informed consent.