The purpose of this study is to use VSTs (virus-specific T cells) from a donor that is a partial HLA (human leukocyte antigen) match with the patient to treat viral infections after an allogeneic hematopoietic stem cell transplant (HSCT). These cells may also have value in CAR-T recipients who have received a product that depletes virus specific T cells.
The patient must have had a myeloablative or non-myeloablative allogeneic HSCT using either bone marrow, single/double umbilical cord blood, or peripheral blood stem cells (PBSC) or CAR T cell product targeting an antigen expressed on virus specific T cells. After a transplant, while the immune system grows back, the patient is at risk for infection. Some viruses can stay in the body for life and are normally controlled by a healthy immune system, but if the immune system is weakened, like after a transplant, they can cause life threatening infections. He/she must have had an infection with one or more of the following viruses -Epstein Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), Human polyomavirus type I (BKV), and human polyomavirus type II (JCV)- that has persisted or recurred despite standard therapy.
In this study, the investigators want to use white blood cells that have been trained to treat viral infections. In an earlier study the investigators showed that treatment with such specially trained T cells has been successful when the cells are made from the transplant donor. However as it takes 1-2 months to make the cells, that approach is not practical for patients who already have an infection. In a subsequent study, the investigators were able to create multivirus-specific T cells (VSTs) from the blood of healthy donors and created a bank of these cells. The investigators then successfully used these banked cells to treat virus infections after a stem cell transplant. In this study the investigators have further modified their production method to decrease the potential side effects and the investigators want to find out if they can use these banked VSTs to fight infections caused by the viruses mentioned above.
Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells or single or double cord blood.
Option 1: Persistent, increasing or recurrent infections despite 7 days of standard therapy;
a. 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, letermovir or cidofovir. 56, 57
i. CMV disease: defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) or the detection of CMV by culture or direct fluorescent antibody stain in broncheoalveolar lavage fluid in the presence of new or changing pulmonary infiltrates or changes consistent with CMV retinitis on ophthalmologic examination.
Patients receiving ATG, Campath or other immunosuppressive T cell monoclonal antibodies within 28 days of screening for enrollment.
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.
Patients who are less than 28 days removed from their allogeneic hematopoietic stem cell transplant or who have received donor lymphocyte infusions (DLI) or CAR-T within 28 days.
Patients with active acute GVHD grades II-IV.
Single group
HLA-matched VSTs
Biological/VaccineAn alternative approach that bypasses the need to grow VSTs for individual patients is to bank closely HLA-matched allogeneic VSTs that could be available as an "off the shelf" product. The HLA-matched VST product is to produce immune activity to CMV, Adv, BK virus and EBV in all recipients. Most recently our group extended this "off the shelf" approach to five viruses using the T cell product manufactured in 10 days. The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. A single infusion produced a cumulative complete or partial response rate of 92% overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (human herpesvirus) (n = 3).
Treatment related adverse events.
The primary objective is to measure the safety of MVSTs based on patients with grades 3-5 non-hematologic adverse events that are at least possibly related to the T cell product.
Number of patients with acute GvHD.
Patients with acute GvHD grades III-IV, summarized by the proportion of patients with acute GvHD grades III-IV among all safety evaluable patients.
Antiviral Response.
The antiviral response is defined as the viral load reduction by at least 50% (partial response) or return to the normal level (complete response) for the treated virus (at least one of the 4 virus types: CMV, EBV, adenovirus, and BK virus). The antiviral response rate is defined as the proportion of subjects with a partial or complete response among all response evaluable patients.
Number of patients with secondary graft failure.
Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in the ANC to less than 500/mm3 for three consecutive measurements on different days, unresponsive to growth factor therapy and persists for at least 14 days in the absence of a known cause such as relapse.
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Baylor College of Medicine
Lead sponsor
The Methodist Hospital Research Institute
Collaborator
