Immunotherapy for Infectious Diseases

256 Onorato and Pollard
Another immunotherapeutic approach to CMV infections in the severely immunosuppressed
is the adoptive transfer of anti-CMV cytotoxic T-cells, which has been employed
in allogeneic bone marrow recipients. This population is particularly prone to CMV
pneumonitis, which is associated with a mortality of 30–60% (35,36). In the first 100
days following transplant, these patients are persistently deficient in class I HLArestricted
CD8� cytotoxic lymphocytes specific for CMV; this deficiency is important in
the pathogenesis of CMV disease in this population (37). Given these observations, Riddell
and colleagues (38) undertook a phase I trial of transfer of clones of CD8� cytotoxic
T-lymphocytes specific for CMV from the marrow donors to the marrow transplant
recipient. Fourteen patients each received a total of four intravenous infusions of these
clones from their donors; the infusions began 30–40 days after transplant and were given
once a week. The infusions themselves were well tolerated. In 11 of the 14 patients,
CMV cytotoxic cells could not be detected prior to the first infusion; in all 11 of these
patients, CMV-specific cytotoxic cells could be detected 2 days after the first infusion,
and all patients had reconstituted CMV-specific cytotoxic T-lymphocytes by days 42–49
post transplant. In a subset of these patients, this reconstitution occurred even in the
absence of detectable CMV-specific CD4� helper cells, which are required for the recovery
of endogenous CMV-specific cytotoxic T-lymphocytes (39). All the patients maintained
cytotoxic T-lymphocyte responses specific for CMV for at least 8 weeks after
completion of T-cell therapy. The magnitude of the responses decreased over time in the
patients who did not recover CD4� T-helper responses specific for CMV compared with
those who did, suggesting that the recovery of a T-helper response may facilitate the
maintenance of transferred CD8� cytotoxic T-lymphocytes. None of the 14 patients
treated developed CMV viremia or disease, although 2 received ganciclovir following
isolation of CMV from surveillance urine cultures.
In summary, various immune-based strategies have been attempted in the treatment
and prophylaxis of viral infections; some hold promise, particularly as potential adjunctive
therapy to antiviral therapies. The complexity of several approaches, particularly
those involving expansion and reinfusion of cell populations, has made them somewhat
impractical for widespread utilization.
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