Immunotherapy for Infectious Diseases
Immunotherapy for Infectious Diseases Immunotherapy for Infectious Diseases
Viral Infections Other than HIV 255 CYTOMEGALOVIRUS INFECTIONS Cytomegalovirus (CMV) infections and end-organ disease following bone marrow or solid organ transplant usually represent reactivation of latent infection; more rarely, they are new infections in a seronegative host. Such infections are associated with a high degree of morbidity and mortality. Although effective antiviral therapies such as ganciclovir and foscarnet are available, they are associated with significant toxicities, and at least in the case of HIV-associated CMV infections, resistance to these agents has been demonstrated. Enhancement of CMV-specific immune response has been another approach to the prevention and treatment of CMV disease in the period of greatest immunocompromise post transplant. The earliest approach involved restoration of humoral immunity by passive immunization with pooled anti-CMV-IgG preparations. Results of trials of such immunization are mixed; although there does not seem to be benefit in bone marrow transplant patients, there is some protection for solid organ transplant patients who receive CMV hyperimmunoglobulin, particularly following renal transplant or for patients who receive an organ from a seropositive donor (29,30). Given the partial success of pooled anti-CMV globulin, a human monclonal antibody to CMV has been developed, MSL 109, directed against the gH glycoprotein of human CMV. The antibody has been shown to have neutralizing activity against both laboratory isolates and clinical isolates of CMV, and seems to be synergistic with ganciclovir or forscarnet in inhibiting laboratory and wild-type CMV isolates in vitro (31,32). Because of this potential synergistic effect with antiviral therapy, and the antibody’s long half-life after intravenous administration (approximately 14 days), several trials were conducted of the administration of MSL 109 with standard therapy (either ganciclovir or foscarnet ) for the treatment of CMV retinitis in patients with the acquired immunodeficiency syndrome. The first was a phase I/II study in which patients received either 0.25, 0.5, 1.0, 2.0, or 5.0 mg/kg as an intravenous infusion every 2 weeks, begun as close as possible to the beginning of maintenance antiviral therapy of the retinitis. There were no significant adverse effects of the antibody infusions, and the median time to progression was 202 days (33). Two larger trials of MSL 109 in CMV retinitis in AIDS were initiated. These parallel studies were AIDS Clinical Treatment Group (ACTG) protocol 266 (a trial of MSL 109 vs placebo with standard therapy for the treatment of newly diagnosed CMV retinitis in patients with AIDS) and the Studies of Ocular Complications of AIDS Monoclonal Antibody Cytomegalovirus Retinitis Trial (SOCA-MACRT), comparing MSL 109 versus placebo with standard therapy for the treatment of newly diagnosed or relapsed CMV retinitis. The SOCA trial showed an unanticipated difference in mortality between the treatment and placebo arms in the relapsed retinitis group, which appeared to be related to the better than expected survival outcomes in the placebo-relapsed group rather than mortality related to the monoclonal antibody itself (34). Given this difference, and the apparent lack of efficacy of MSL-109 in the SOCA trial, the ACTG trial was terminated early, before adequate numbers had been accrued to be able to detect a difference between treatment and placebo groups. This monoclonal antibody is no longer being pursued as a potential therapy for CMV infections.
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. REFERENCES 1. McIntosh K. Respiratory syncytial virus infection in infants and children: diagnosis and treatment. Pediatr Res 1987; 9:191–196. 2. La Via WV, Marks MI, Stutman HR. Respiratory syncytial virus puzzle: clinical features, pathophysiology, treatment and prevention. J Pediatr 1992; 121:503–510. 3. Bruhn FW, Mokowsky W, Kransinski K, Lawrence R, Welliver R. Apnea associated with respiratory syncytial virus infection in young infants. J Pediatr 1977; 90:382–386. 4. Hall CB, McBride JT, Gala CL, Hildreth SW, Schnabel KC. Ribavirin treatment of respiratory syncytial virus infection in infants with underlying cardiopulmonary disease. JAMA 1985; 254:3047–3051. 5. Hall CB, Powell KR, MacDonald NE, et al. Respiratory syncytial virus infection in children with compromised immune function. N Engl J Med 1986; 315:77–81. 6. Whimbey E, Chamlin RE, Couch RB, et al. Community respiratory virus infections among hospitalized adult bone marrow transplant recipients. Clin Infect Dis 1996; 22:778–782. 7. PREVENT Study Group. Reduction of respiratory syncytial virus hospitalization among premature infants and infants with bronchopulmonary dysplasia using respiratory syncytial virus immune globulin prophylaxis. Pediatrics 1997; 99:93–99.
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Viral Infections Other than HIV 255<br />
CYTOMEGALOVIRUS INFECTIONS<br />
Cytomegalovirus (CMV) infections and end-organ disease following bone marrow<br />
or solid organ transplant usually represent reactivation of latent infection; more rarely,<br />
they are new infections in a seronegative host. Such infections are associated with a<br />
high degree of morbidity and mortality. Although effective antiviral therapies such as<br />
ganciclovir and foscarnet are available, they are associated with significant toxicities,<br />
and at least in the case of HIV-associated CMV infections, resistance to these agents<br />
has been demonstrated.<br />
Enhancement of CMV-specific immune response has been another approach to the<br />
prevention and treatment of CMV disease in the period of greatest immunocompromise<br />
post transplant. The earliest approach involved restoration of humoral immunity by<br />
passive immunization with pooled anti-CMV-IgG preparations. Results of trials of such<br />
immunization are mixed; although there does not seem to be benefit in bone marrow<br />
transplant patients, there is some protection <strong>for</strong> solid organ transplant patients who<br />
receive CMV hyperimmunoglobulin, particularly following renal transplant or <strong>for</strong><br />
patients who receive an organ from a seropositive donor (29,30).<br />
Given the partial success of pooled anti-CMV globulin, a human monclonal antibody<br />
to CMV has been developed, MSL 109, directed against the gH glycoprotein of<br />
human CMV. The antibody has been shown to have neutralizing activity against both<br />
laboratory isolates and clinical isolates of CMV, and seems to be synergistic with ganciclovir<br />
or <strong>for</strong>scarnet in inhibiting laboratory and wild-type CMV isolates in vitro<br />
(31,32).<br />
Because of this potential synergistic effect with antiviral therapy, and the antibody’s<br />
long half-life after intravenous administration (approximately 14 days), several trials<br />
were conducted of the administration of MSL 109 with standard therapy (either ganciclovir<br />
or foscarnet ) <strong>for</strong> the treatment of CMV retinitis in patients with the acquired<br />
immunodeficiency syndrome. The first was a phase I/II study in which patients received<br />
either 0.25, 0.5, 1.0, 2.0, or 5.0 mg/kg as an intravenous infusion every 2 weeks, begun<br />
as close as possible to the beginning of maintenance antiviral therapy of the retinitis.<br />
There were no significant adverse effects of the antibody infusions, and the median<br />
time to progression was 202 days (33). Two larger trials of MSL 109 in CMV retinitis<br />
in AIDS were initiated. These parallel studies were AIDS Clinical Treatment Group<br />
(ACTG) protocol 266 (a trial of MSL 109 vs placebo with standard therapy <strong>for</strong> the<br />
treatment of newly diagnosed CMV retinitis in patients with AIDS) and the Studies of<br />
Ocular Complications of AIDS Monoclonal Antibody Cytomegalovirus Retinitis Trial<br />
(SOCA-MACRT), comparing MSL 109 versus placebo with standard therapy <strong>for</strong> the<br />
treatment of newly diagnosed or relapsed CMV retinitis. The SOCA trial showed an<br />
unanticipated difference in mortality between the treatment and placebo arms in the<br />
relapsed retinitis group, which appeared to be related to the better than expected survival<br />
outcomes in the placebo-relapsed group rather than mortality related to the monoclonal<br />
antibody itself (34). Given this difference, and the apparent lack of efficacy of<br />
MSL-109 in the SOCA trial, the ACTG trial was terminated early, be<strong>for</strong>e adequate<br />
numbers had been accrued to be able to detect a difference between treatment and<br />
placebo groups. This monoclonal antibody is no longer being pursued as a potential<br />
therapy <strong>for</strong> CMV infections.