Immunotherapy for Infectious Diseases

Virus-Associated Malignancies 261
can be recognized when they are infected by a virus. For activating (priming) naive
CTL precursors, the peptides must be presented by professional antigen-presenting
cells (APCs), which can also provide the necessary costimulatory signals (i.e., interaction
of B7 with CD28 or CD40 with CD40L on APC and T-cells, respectively) (6). If
the T-cell receptor is engaged without costimulatory signals, T-lymphocytes can become
anergized. Activated CTLs do not need the costimulatory molecules to exert their effector
functions, namely, cytolysis or induction of apoptosis of the target cell.
CD4� Th-lymphocytes recognize exogenous antigens that are phagocytosed,
processed, and presented in the context of MHC class II. Only APCs that are MHC
class II-positive can activate CD4� Th-lymphocyte precursors. Their major antiviral
effect appears to be secreting cytokines and activating other effector cells, such as
B-lymphocytes and CTLs. They may also have indirect antitumor activity via release
of toxic cytokines (e.g., tumor necrosis factor-� [TNF-�]). CD4� Th-lymphocyte help
is crucial for the maintenance of an effective CTL response. When the infected cell is
MHC class II-positive, CD4� T-lymphocytes can also be cytolytic to the target cells
(7). This function has been clearly demonstrated for herpesvirus infections including
cytomegalovirus, herpes simplex virus, varicella-zoster virus, and EBV (8).
Endogenously synthesized antigens are generally thought to be presented as peptides
on MHC class I molecules to CD8� CTLs (i.e., the cytosolic pathway), whereas
exogenous antigens are phagocytosed and presented in an MHC class II context to
CD4� Th-lymphocytes (i.e., the endosomal pathway). Alternatively, APCs can phagocytose
antigens from virus-infected cells and present them on MHC class I molecules
via exogenous pathways (6). Viruses possess mechanisms to enter the cytosol, and
virion proteins, although not endogenously synthesized, can gain access to the MHC
class I pathway (9,10). Thus, in some instances, the immune system might eradicate
infected cells before the viral genome is expressed and progeny viruses produced.
IMMUNOTHERAPY
The goal of immunotherapy is to overcome the deficits of the host or the tumor itself
and activate an effective immune response to the tumor. In the case of virus-associated
malignancies, immunotherapeutic strategies can be either prophylactic (prevention of
infection or prevention of tumor outgrowth in already infected individuals) or therapeutic
(targeting the immune response against viral proteins expressed in tumor cells).
In both applications, CTLs are regarded as the most important effector arm of the
immune response against tumor or virus-infected cells, and they may be activated in
vivo or ex vivo (Fig. 2). In vivo approaches such as vaccination aim to evoke an
immune response by administration of an immunogen such as a peptide or DNA
directly into patient. In the ex vivo approach, CTLs are activated and expanded in vitro,
in a culture environment conducive to CTL growth, and then adoptively transferred into
a recipient.
A tumor cell may fail to activate an effective immune response in the host for a number
of reasons. First, tumor cells may fail to express an antigen that is perceived as foreign.
In virus-associated malignancies, peptides derived from viral proteins can provide
the target epitopes for CTLs. Second, tumor cells may fail to provide the costimulatory
signals needed to activate CTLs. Optimal CTL induction can be achieved with professional
APCs (e.g., DCs). Third, tumor cells may have mechanisms that inhibit the