Purpose

This Phase I dose-escalation trial is designed to evaluate the safety of rapidly generated multivirus-specific T-cell products with antiviral activity against CMV, EBV, adenovirus, HHV6, BK virus, JC virus, and human parainfluenza-3 (HPIV3), derived from eligible HSCT donors. In this trial, the investigators will utilize a rapid generation protocol for broad spectrum multivirus-specific T cells for infusion to recipients of allogeneic hematopoietic stem cell transplant (HSCT), who are at risk of developing EBV, CMV, adenovirus, HHV6, BKV and/or HPIV3, or with PCR/culture confirmed infection(s). These cells will be derived from HSCT donors, and the study agent will be assessed at each dose for evidence of dose-limiting toxicities (DLT). This study will have two arms: Arm A will include patients who receive prophylactic treatment, and Arm B will include patients who receive VSTs for one or more active infections with targeted viruses. Determination of the study arm will be determined by the patient's clinical status. Study arms will each be analyzed for safety endpoints and secondary endpoints.

Conditions

Eligibility

Eligible Ages
All ages
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

Recipient Inclusion Criteria at the time of VST infusion

1. Prior myeoloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells no earlier than 5 days prior to the date of VST infusion, AND

2. Prophylaxis for patients at risk of CMV, adenovirus, EBV, HHV6, BK virus, JC virus, and/or HPIV3 infection, OR

3. Treatment of reactivation or active infection which is defined for each virus as below

4. Treatment may be given to eligible patients with a single or multiple infections. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll.

5. Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day prednisone or equivalent.

6. Karnofsky/Lansky score of ≥ 50

7. Bilirubin <2x upper limit normal

8. AST < 5 x upper limit normal

9. Serum creatinine < 2 x upper limit normal

12. Hgb >8.0 g/dL(level can be achieved with transfusion)

13. Pulse oximetry of > 90% on room air

14. Available multivirus-specific T cells (VSTs)

15. Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen).

16. Written informed consent and/or signed assent line from patient, parent or guardian.

Exclusion Criteria

Recipient Exclusion criteria at the time of VST infusion:

1. Patients receiving ATG, Campath, Basiliximab, or other immunosuppressive T cell monoclonal antibodies within 28 days of screening for enrollment. In patients who have received these therapies as part of their conditioning regimens, 28 days must have elapsed since the final dose before VST may be given.

2. Patients with other uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment.

Progressing infection is defined as worsening clinical symptoms, physical findings, vital sign abnormalities (including hemodynamic instability), and/or microbiologic or radiographic findings attributable to infection. Persisting fever without other signs /symptoms or laboratory evidence will not be interpreted as progressing infection.

3. Patients who have received donor lymphocyte infusion (DLI) or other cellular therapies (with the exception of the allogeneic cells relating to the transplantation) within 28 days.

4. Patients with active acute GVHD grades II-IV.

5. Active and uncontrolled relapse of malignancy

6. Patients with Grade >3 hyperbilirubinemia

7. Patients who have received investigational (IND) product within 28 days of screening for enrollment under this study

Study Design

Phase
Phase 1
Study Type
Interventional
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Prophylactic and treatment
Virus Specific T cells (VSTs) for prophylactic and treatment of active viral infection(s) after HSCT. 3 different dose levels starting with 1 x 10E7 /m2 (a T cell number more than an order of magnitude lower than that administered at the time of an unmanipulated marrow infusion), followed by 2 x 10E7/m2 and a final dose 5 x 10E7 VSTs/m2
  • Biological: Virus Specific T cells (VSTs)
    Pediatric and adult patients following any type of allogeneic transplant (HSCT) will receive VSTs as prophylaxis or treatment of reactivation or infection with CMV, adenovirus, EBV, HHV6, BK virus, JC virus, and/or HPIV3). The goal of this cell infusion will be to initiate an immune response against viral infections after HSCT. VSTs will be generated using clinical grade overlapping peptides (Pepmixes) to directly stimulate PBMCs, growth promoting cytokines and the G-Rex culture device optimized for T cell expansion. Donor T-cells will be stimulated with overlapping peptide libraries encompassing pp65 and IE-1 (CMV), Hexon and Penton (Adenovirus), LMP2 and EBNA-1 (EBV), LgT and VP1 (BK virus), U54 and U90 (HHV6B), and Mat and NP (HPIV3).

Recruiting Locations

Children's National and nearby locations

Childrens National Medical Center
Washington, District of Columbia 20010
Contact:
Fahmida Hoq, MBBS, MS
202-476-3634
fhoq@cnmc.org

More Details

NCT ID
NCT03180216
Status
Recruiting
Sponsor
Children's National Research Institute

Study Contact

Michael Keller, MD
202-476-5843
MKeller@childrensnational.org

Detailed Description

Viral infections are normally controlled by T-cell immunity and are a cause of significant morbidity and mortality during the period of immune recovery after hematopoietic stem cell transplantation (HSCT). Risk for infection is impacted by the degree of tissue mismatch between donor and recipient and the immune status of the donor, including the degree and length of immunosuppression following transplantation. Reactivation of latent viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Human Herpesvirus 6B (HHV6) are common and often cause symptomatic disease. Reactivations of the polyomaviruses BK virus and JC virus are also common and frequently cause renal disease including hemorrhagic cystitis and less commonly neurologic disease (pervasive multifocal leukoencephalopathy). Respiratory viruses such as adenovirus and human parainfluenza also frequently cause infection. Antiviral pharmacologic agents are only effective against some of these viruses; their use is costly, and associated with significant toxicities and the outgrowth of drug-resistant mutants. As delay in recovery of virus-specific cellular immune response is clearly associated with viral reactivation and disease in these patients, cellular immunotherapy to restore viral-specific immunity is an attractive option that has already been successfully used to target several of these viruses.

To broaden the specificity of single T cells lines to include the three most common viral pathogens of stem cell recipients, the investigators reactivated CMV and adenovirus-specific T cells by using mononuclear cells transduced with a recombinant adenoviral vector encoding the CMV antigen pp65 (Ad5f35CMVpp65). Subsequent stimulations with EBV-LCL transduced with the same vector both reactivated EBV-specific T cells and maintained the expansion of the activated adenovirus and CMV-specific T cells. This method reliably produced T cells with cytotoxic function specific for all three viruses, which the investigators infused into 14 stem cell recipients in a Phase I prophylaxis study. The investigators observed recovery of immunity to CMV and EBV in all patients but an increase in adenovirus-specific T cells was only seen in patients who had evidence of adenovirus infection pre-infusion. A follow-up study in which the frequency of adenovirus-specific T cells was increased in the infused T cells produced similar results, thus highlighting the importance of endogenous antigen to promote the expansion of infused T cells in vivo. Nevertheless, all patients in both clinical trials with pre-infusion CMV, adenovirus or EBV infection or reactivation were able to clear the infection, including one patient with severe adenoviral pneumonia requiring ventilatory support. T cells recognizing multiple antigens can therefore produce clinically relevant effects against all three viruses.

Recent studies have extended the number of targeted viruses, and included HHV6B, BK virus, and Varicella-zoster virus (VZV). In a recent study, 11 patients were treated with VST targeting 5-viruses (CMV, EBV, Adv, HHV6B, BKV) which were generated using a rapid protocol with overlapping peptides encompassing 12 viral protein. VST infusion resulted in a 94% antiviral response rate in these patients (complete or partial responses against CMV=3/3, EBV=5/5, Adv=1/1, HHV6B=2/2, BKV=6/7). Two of the patients who received 5-virus VST developed transplant-associated microangiopathy, which was deemed secondary to HSCT and unrelated to VST infusion. One of these patients developed grade II skin GVHD, which improved with topical therapy. In another recent study, ten adult patients were prophylactically treated with VST specific for CMV, EBV, Adv, and Varicella (VZV). These VSTs were generated using donor-derived dendritic cells which were infected with either Ad5f35-pp65 or with varivax vaccine, and were then pooled and used to stimulate donor PBMCs. All ten patients were protected against EBV, Adv, and VZV. Six patients developed CMV reactivation, but only one required antiviral therapy. Of these 10 patients, 7 developed acute or chronic GVHD, though compared to a non-treated group at the same institution, the rate of GVHD did not differ significantly. Thus, it has been possible to target an extended panel of viruses with a single VST product.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.