Immunotherapy for Infectious Diseases

Virus-Associated Malignancies 263
of functional genes may improve the activity of infused CTLs (16). Thus, adoptive
therapy with virus-specific T-lymphocytes potentially offers maximal therapeutic efficiency
with minimal toxicity. We have used virus-specific CTLs for the prevention and
treatment of EBV-associated malignancies in stem cell recipients, who are immunosuppressed,
as well as in patients with relapsed EBV-positive Hodgkin’s disease, whose
tumors secrete inhibitory factors.
Vaccination
Peptides
Short, immunogenic peptides from virus-encoded proteins can be used for vaccination
(17). A number of naturally presented viral CTL epitopes have been identified by
various techniques (17). For example, a CTL response against an HPV-16-E7-encoded
peptide was occasionally detected in cervical carcinoma patients (18,19), suggesting
the presence of a natural CTL-mediated immunity against HPV-16 in patients with cervical
cancer. Similarly, T-lymphocytes from patients with HBV infection recognized
the immunogenic peptides of HBV (20). These specific but ineffective CTL responses
might be augmented by additional in vivo stimulation with the immunogenic peptide.
Vaccination with a naturally processed and immunogenic peptide in vivo was initially
tested in murine models of lymphocytic choriomeningitis virus (21) and Sendai
virus (22). An MHC class I binding peptide expressed by a recombinant vaccinia virus
or injected in an adjuvant protected the mice against a challenge with a lethal dose of
virus. Furthermore, vaccination with a peptide derived from HPV-16-E7 oncoprotein
prevented the outgrowth of an HPV-16-induced tumor in mice (23). However, the
method of administration was found to be important for peptide immunotherapy (12).
A specific deletion of peptide-specific CTL was observed after injection of a peptide
subcutaneously (24). When the same peptide was loaded onto DCs or expressed as a
transgene by a recombinant adenovirus vector, CTL response was detected (12). Coadministration
of recombinant IL-12 or addition of a helper peptide to a CTL peptide can
also reverse the anergic state and help prime CTLs against the peptide (25). These
results indicate the importance of recruiting Th1 cells to the vaccination site. A persistent
problem with single immunogenic peptides is the risk of mutations that alter the
epitope, allowing the virus or tumor cell to evade the immune response. A second problem
with peptides in general is that they must be tailored to suit the patient’s HLA type.
Genetic Immunization
Immunotherapy by in vivo transfer of DNA encoding virus- or tumor-associated
peptides or antigens is based on the rationale that qualitatively and quantitatively
increased peptide presentation will lead to effective activation of both cytotoxic T-cell
response and a humoral response (26). DNA vaccination may be used to induce immune
responses against predetermined peptides, an entire antigen, or multiple antigens. In
contrast to peptide vaccination, DNA vaccination with an entire antigen results in intracellular
processing and presentation of immunogenic peptides, so that the HLA type is
less restrictive. The development of a protective immune response by immunization
with a genetic vaccine was initially demonstrated in mice that had received intramuscular
injections of naked plasmid DNA encoding the influenza virus nucleoprotein
(NP). Both NP-specific antibody and CTL responses were generated, with resultant