Immunotherapy for Infectious Diseases

Virus-Associated Malignancies 265
Inducing immune responses to multiple peptides is a major goal of research in
genetic immunization. The string-bead approach, which links multiple different CTL
or T-helper epitopes, is one of the methods proposed. Such multiepitope (polytope)
vaccines might induce immunity against multiple antigenic targets, multiple strain variants,
or multiple pathogens (45). The polytope vaccine hypothesis was recently validated
in a study in which a recombinant vaccinia virus containing 10 contiguous
minimal murine CTL epitopes was used to induce primary CTL responses to all 10 epitopes
in mice (46).
Dendritic Cell Vaccines
DCs are the most potent antigen-presenting cells yet identified (47). They are efficient
in priming naive T-lymphocyte precursors, as they possess the costimulatory signals
and secrete the cytokines required for this immune response. The development of
techniques to generate adequate numbers of DCs from peripheral blood precursors or
bone marrow progenitors has led to application of these cells in immunotherapy (48).
In general, peptide-pulsed DCs are more effective in eliciting immune responses than
are peptides alone (49–51). Introduction of antigen-coding DNA into the cytoplasm of
DCs for endogenous processing and presentation allows CTL activation that is independent
of HLA type. Such transduction is possible with either physical methods (e.g.,
liposomes) or viral vectors (e.g., adenovirus vectors) (52–54). When the use of DNA
vaccination against viral oncoproteins (e.g., E6 and E7 of HPV) raises safety issues,
RNA-loaded APCs may offer a useful alternative (55). Clinical trials of DCs loaded
with tumor antigens are in progress (48).
VIRUS-ASSOCIATED MALIGNANCIES
Epstein-Barr Virus
EBV, also designated human herpesvirus 4, is associated with malignancies of
B-cells, epithelial cells, T-cells, natural killer cells, and muscle (56,57). The development
of EBV-positive tumors is associated with the latent life cycle of the virus during which
it expresses up to nine viral proteins that provide targets for CTLs.
Adoptive Immunotherapy
LPDs of stem cell transplant recipients have provided an excellent system for testing
the biologic efficacy of ex vivo expanded, adoptively transferred antigen-specific
CTL lines. LPD represents the most immunogenic tumor (type 3 latency) among EBVrelated
malignancies, as all EBV latency-associated proteins are expressed by the
virally transformed lymphocytes. Virus-infected B-cells expressing type 3 latency do
not evade the immune response and are seen only in severely immunocompromised
individuals. For example, EBV-LPD occurs in up to 20% of recipients of T-celldepleted
stem cells from HLA-mismatched or unrelated donors. No antiviral agents are
reproducibly effective against EBV-LPD. Immunotherapy with unmanipulated donor
leukocytes, although effective in some cases, is associated with a high incidence of disease
progression, and survivors have a high incidence of graft-versus-host disease
(GvHD) (58). We have shown that LPD can be prevented or eradicated and GvHD
avoided by using selectively expanded EBV-specific CTLs either prophylactically or as
treatment for overt disease (59). EBV-transformed B-cell lines are relatively easy to