This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT Allogeneic stem cell transplantation is the treatment of choice for selected patients with high-risk hematologic malignancies. However a significant proportion of patients - especially non-Caucasians - lack a marrow or peripheral blood stem cell donor. Umbilical cord blood (CB) has therefore emerged as an important alternative source of stem cells for allotransplant patients. The major advantages of CB transplants (CBT) compared to unrelated marrow include more rapid procurement of the graft, the requirement for less stringent HLA matching (tissue typing), the higher likelihood of finding a match for ethnic minorities, and a decreased incidence of graft versus host disease (GVHD). However, one of the major disadvantages of CB is the delayed immune recovery due to the small numbers of T cells transferred and the absence of memory T cells within the donor grafts, Consequently, CB recipients are susceptible to an array of viral and other infections that are the leading cause of death in these patients. Cytomegalovirus and Adenovirus are two of the most common viruses that can cause problems after a cord blood transplant. Investigators have previously shown that it is possible to grow special T cells called virus-specific cytotoxic T lymphocytes (CTL) from the peripheral blood of adult transplant donors that will prevent and treat these viral infections when they are given back to the patient after bone marrow transplant. In this study, investigators will see if they can use a similar approach and make CTLs from cord blood to give to patients after cord blood transplant to prevent reactivation and infection with CMV and adenovirus. Virus specific CTL lines will be grown from normal umbilical cord blood units and frozen. To make the CTL they will first infect blood cells called dendritic cells with a specially produced adenovirus (a vector) that also carries part of the CMV gene. This is a disabled virus that cannot reproduce itself once infection has occurred so it cannot spread. These infected dendritic cells are irradiated and are then used to stimulate the T cells to respond to adenoviruses and CMV, and kill the cells infected with these viruses. The investigators will then give a second stimulation to the T cells, using irradiated B cells (also made from the same cord blood unit) which are also infected with EBV in addition to the same vector. Once we have made sufficient number of T cells they will test them to make sure they kill cells infected with these viruses and freeze them. The primary objective is to determine whether this strategy is feasible and safe. One risk is that because the T cell are donor-derived they may attack the subject and cause a condition called graft versus host disease (GVHD). We will closely monitor for this complication. Secondary objectives are to determine the effects of the T cell infusion on the virus infection and to see if the recipients can stay immune to these viruses. I. HYPOTHESIS In this trial, we will evaluate whether the administration of cord blood donor derived CTLs to recipients of cord blood transplants with or at risk for CMV and AdV will be able to clear or prevent reactivation or infection with these two viruses. The CTL product that we will use in this study is manufactured using antigen presenting cells transduced with an adenoviral vector encoding pp65 as we used in a previous study (RAC#0304-579). In this previous study the CTL were generated from donor peripheral blood and the infused donor-derived CTLs had antiviral activity after administration to bone marrow and peripheral blood stem cell transplant recipients. The study agent for this new study for patients after cord blood transplant will be assessed primarily for safety (stopping rules defined) and as secondary objectives antiviral activity and ability to reconstitute antiviral immunity. II.
SPECIFIC AIMS The primary purpose or objective of the study is to determine the safety, toxicity and maximum tolerated dose (MTD) of one intravenous injection of donor-derived cytotoxic T lymphocytes (CTLs) specific for CMV and Adenovirus given to patients with or at risk for CMV and adenovirus disease after cord blood transplant. The secondary objectives will evaluate the impact of these CTLs on CMV/AdV-specific T-lymphocyte immune reconstitution and the efficacy of recovery of virus-specific immunity after CTL infusion and its correlation with protection from viral infection/disease. We will also evaluate the efficacy of recovery of virus-specific immunity after CTL infusion and its correlation with viral clearance and/or protection from viral infections/disease.
Showing the most recent 10 out of 459 publications
