Immunotherapy for Infectious Diseases

254 Onorato and Pollard
patients with EBV-related lymphoproliferative disease. Functional assays of these activated
cells demonstrated preferential cytotoxicity against autologous EBV-transformed
cells and some activity against allogenic EBV� targets. All four patients treated with
these activated PMBCs had durable regressions of the lymphoma (20).
Another approach to the treatment of EBV-related lymphoproliferative disorders,
as well as other types of lymphoma and leukemias, has been the administration of
monoclonal antibody to CD20 antigen (rituximab) found on normal and malignant
B-lymphocytes, producing antibody-dependent and complement-mediated cytotoxicity
in these cells. Although the utility of this approach extends beyond EBV-associated
lymphoma, it has been used along with infusions of irradiated donor-derived lymphocytes
with some success in treatment of EBV-related lymphoproliferative disorders
following allogenic stem cell transplantation. The two patients treated experienced disappearance
of the monoclonal B-cell populations and normalization of elevated EBV
DNA titers (21). A report of three patients treated with rituximab for lymphoproliferative
disease following lung transplant suggests some efficacy in this population as
well, with two complete remissions in the three patients treated (22).
IMMUNE-BASED APPROACHES TO HEPATITIS B
Although pharmacologic agents with activity against hepatitis B are in development,
there has been interest in immunologic therapy of chronic hepatitis secondary to hepatitis
B, potentially as an adjunct to antiviral therapy. Administration of cytokines (such
as IL-12) and antibody to surface antigen are two approaches that have been studied.
Longitudinal studies of chronic carriers of hepatitis B virus (HBV) suggest a role
for IL-12 in viral clearance. Not only do HBV carriers have higher levels of IL-12 than
controls, but further increases above baseline are noted in HBV carriers who go on to
develop anti-HBe and clear HBV compared with those who have persistent HBV replication
(23). Based on this observation, as well as evidence from transgenic mouse models
of hepatitis B infection, it is postulated that the antiviral effect of IL-12 is mediated
by interferon-�, IL-2, and tumor necrosis factor-� (TNF-�) released by HBV-specific
cytotoxic T-lymphocytes (CTLs) and that the result is suppression of HBV gene expression
in infected hepatocytes by noncytolytic mechanisms (24–27). A small trial of
IL-12 with or without lamivudine as part of concurrent antiretroviral therapy for
chronic hepatitis B infection in patients coinfected with HIV is currently accruing. It
is hoped that the combination of better antiviral therapies for hepatitis B and stimulation
of immune responses such as enhancement with IL-12 will be an effective strategy
for chronic hepatitis.
Another approach to the treatment of chronic hepatitis B involves a human monoclonal
antibody to hepatitis B surface antigen, OST-577 (Protein Design Labs). In a
phase I/II trial of this antibody in patients with chronic HBV infection, subjects received
either 0.5, 1.0, or 2.0 mg/kg intravenously on days 0, 1, 3, 7, 14, 21, and 35. The lower
doses were well tolerated; however, two subjects in the 2.0-mg/kg cohort developed
hypotension that was thought to be related to immune complex deposition. Both patients
tolerated dose reduction without further hypotensive episodes. Serum animotransferase
levels and serum HBV DNA were measures of efficacy; mean reductions of HBV DNA
by 75% and serum SGOT by 49% were seen (28). Larger studies of this antibody are
needed to establish its role in the therapy of chronic HBV infection.