Antiviral Cellular Therapy for Enhancing T-cell Reconstitution Before or After Hematopoietic Stem Cell Transplantation

The primary purpose of the study is to evaluate whether most closely HLA-matched
multivirus-specific T cell lines obtained from a bank of allogeneic virus-specific T cell
lines (VSTs) have antiviral activity against three viruses: EBV, CMV and adenovirus.

Reconstitution of anti-viral immunity by donor-derived VSTs has shown promise in preventing
and treating infections associated with CMV, EBV and adenovirus post-transplant. However, the
time required to prepare patient-specific products and lack of virus-specific memory T cells
in cord blood and seronegative donors, limits their value. An alternative is to use banked
partially HLA-matched allogeneic VSTs. A prior phase II study at Baylor College of Medicine
using trivirus-specific VSTs generated using monocytes and EBV-transformed B cells
gene-modified with a clinical grade adenoviral vector expressing CMV-pp65 to activate and
expand specific T cells showed the feasibility, safety and activity of this approach for the
treatment of refractory CMV, EBV and Adenovirus infections. More recent protocols utilizing
synthetic viral peptide pools allow ex vivo expansion of T-cells targeting multiple viral
antigens in 10-12 days without use of viral transduction.

The study will evaluate whether partially-HLA matched allogeneic multivirus-specific VSTs,
activated using overlapping peptide libraries spanning immunogenic antigens from CMV,
adenovirus and EBV, will be safe and produce anti-viral effects in immunodeficient recipients
infected with one of more of the targeted viruses that are persistent despite conventional
anti-viral therapy.

This study will evaluate safety and efficacy of partially-matched VST therapy in A) patients
who have persistent viral infections in the post-HSCT period, and B) patients with primary
immunodeficiency conditions who have persistent viral infections and have not undergone HSCT.

The study agent will be assessed for safety and antiviral activity.

Inclusion Criteria

Patients who have received any type of allogeneic transplant or who have a primary
immunodeficiency disorder will be eligible if they have CMV, adenovirus, and/or EBV
infection/disease with failure of treatment after 7 days of standard therapy OR if unable
to tolerate standard therapy.

- Patients must meet one of the following criteria:

- Recipient of prior myeloablative or non-myeloablative allogeneic hematopoietic
stem cell transplant using either bone marrow or peripheral blood stem cell or
single or double cord blood within the previous 18 months, OR

- Have a diagnosed primary immunodeficiency disorder (as defined by clinical and
laboratory evaluations) and not undergone HSCT.

- Treatment of the following persistent or relapsed infections despite standard therapy:

- CMV: Treatment of persistent or relapsed CMV disease or infection after standard
therapy. For CMV infection, standard therapy is defined as antiviral therapy with
ganciclovir, foscarnet or cidofovir for at least 14 days.

- Adenovirus: Treatment of persistent or relapsed adenovirus infection or disease
despite standard therapy. Standard therapy is defined as antiviral therapy with
cidofovir or brincidofovir.

- EBV: Treatment of persistent or relapsed EBV infection despite standard therapy.

For EBV infection, standard therapy is defined as rituximab given at 375 mg/m2 in patients
for 1-4 doses with a CD20+ tumor.

Additional Inclusion Criteria:

- Patients with simultaneous infections with CMV, EBV and/or Adenovirus infections are
eligible if one or more infection(s) is persistent or relapsed despite standard
therapy as defined above. Patients with multiple infections with one or more
reactivation and one or more controlled infection are eligible to enroll.

- Clinical status at enrollment that allows tapering of steroids to equal or less than
0.5 mg/kg/day prednisone (or equivalent) prior to infusion of the VST doses.

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

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

Exclusion Criteria

- Patients receiving ATG, Campath, Basiliximab or other immunosuppressive monoclonal
antibodies targeting T-cells within 28 days of screening for enrollment.

- Patients who have received donor lymphocyte infusion (DLI) or other experimental
cellular therapies within 28 days.

- Current therapy with ruxolitinib or other JAK inhibitors within the previous 3 days.

- Patients with other uncontrolled infections, defined as bacterial or fungal infections
with clinical signs of worsening despite standard therapy. 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 hemodynamic instability, worsening physical signs,
or radiographic findings attributable to infection. Persisting fever without other
signs or symptoms will not be interpreted as progressing infection.

- Patients with active and uncontrolled relapse of malignancy (if applicable).