This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.ABSTRACTAdenoviruses (Ad) are non-enveloped, lytic, DNA viruses capable of infecting most animal species. The pathogenicity of Adenovirus varies according to group and type and, although acute infection is sometimes severe, it is rarely fatal in otherwise healthy adults. Thus, in normal individuals, the antiviral immune response of the host controls the extent of virus replication and spread. However, Ads are one of a group of opportunistic pathogens of immunosuppressed patients, where severe, prolonged and even fatal infections are common. The frequency of severe Ad disease is increasing in association with growing numbers of immunocompromised individuals, and fatality rates as high as 50% to 80% have been reported {Anderson & Jordan 1990 4252/id}{Carter, Karpen, et al. 2002 4259 /id}. While there are anecdotal reports of adenoviral disease responses to Cidofovir, {Carter, Karpen, et al. 2002 4259 /id} there are no approved antiviral agents with proven efficacy, nor are there currently any prospective randomized controlled trials of potentially useful anti-Ad therapies. Virus-specific CTL proven successful in the prevention and treatment of EBV and CMV-associated diseases in hematopoietic stem cell transplant (SCT) recipients. Since it is possible to transfer cell-mediated responses to EBV and CMV, we wish to evaluate this approach in patients with Ad infection by infusing donor-derived, Ad-specific CTL. In preclinical studies we can generate CTLs containing a CD4 and CD8-specific component using this method and have been successful in identifying the hexon protein as a dominant T cell target antigen. THe goal of our individuals, the antiviral immune response of our clinical study is to generate Ad-specific cytotoxic T-cells and adoptively transfer them as Adenoviral prophylaxis to patients at risk of Adenoviral infection after allogeneic stem cell transplant. These are patients who receive either a T cell depleted transplanted from a mismatched related donor or an unrelated donor (MUD) or an anti T cell antiboy such as Campath or ATG in conditioning. One dose of Ad-specific CTL will be given from 30 days after transplant and toxicity will be assessed by standard NIH criteria. Antiviral prophylaxis will not be used, but patients will be monitored for Ad reactivation by screening blood, stool, and urine by adenoviral PCR assay. Unlike CMV and EBV which are persistent viral infections, adenoviruses produce only transient infection. This may have a substantial impact on the survival and expansion of the infused cells. Hence one of the aims of this study is to assess the effects of adenovirus infection on CTL survival and expansion in vivo. While patients will receive a single dose of adenovirus specific CTL regardless of their adenoviral status, a second dose of CTL will be administered to patients who become adenovirus infected 4 weeks or more after the initial dose of CTL. Adenovirus infection will be defined as the presence of adenoviral positivity as detected by PCR or culture from ONE site such as stool or blood or urine. The functionality of this seconddose compared to the behavior of the first will provide important information about the correct timing of AdCTL administration after stem cell transplant. Since no effective alternate treatment for adenoviral infection exists (in contrast to CMV) this protocol should not compromise patient safety.
SPECIFIC AIMS To determine the safety, toxicity and maximum tolerated dose (MTD) of one intravenous injection of donor-derived adenovirus-specific cytotoxic T lymphocytes (CTLs) given as adenovirus prophylaxis to patients at risk of developing adenorius infection after allogeneic stem cell transplant.To evlauate the recovery of virus-specific immunity after CTL infusion and assess its correlation with protection from viral load and disease.To obtain preliminary information regarding whether the presence of antigen is required for Ad-specific CTL persistence in vivo.
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