Immunotherapy for Infectious Diseases

Virus-Associated Malignancies 267
Recipients of solid organ transplants may be at particularly high risk for EBV-LPD
if they are seronegative prior to transplantation or if they receive organs, such as gut,
that carry a high B-cell load, or if they receive prolonged, intensive immunosuppressive
therapy for repeat episodes of graft rejection. Surprisingly, it has been possible to
generate EBV-specific CTL lines from organ recipients even after they have developed
lymphoproliferative disease. This suggests that EBV-specific CTL precursors are present
in the circulation but are unable to expand in vivo during treatment with immunosuppressive
drugs. If such cells are moved to a supportive culture environment, they
can respond to activation and proliferation signals. In the case of seronegative recipients,
it may be possible to activate CTLs by using APCs such as DCs, since they are
able to activate CTLs from naive precursors in vitro (47). Prophylaxis with CTLs is
probably not an option in these patients, since with time, in the absence of viral antigen
and the presence of immunosuppressive drugs, the infused CTL may be lost. However,
because regular monitoring of the virus load can permit early intervention, CTLs
should be prepared in advance for patients with a high-risk status and then infused
when virus DNA appears or they seroconvert.
Patients with immunodeficiency disorders are also at increased risk for EBV-LPD.
As with solid organ recipients, it has been possible to generate EBV-specific CTLs
from some of these patients and to use them as therapeutic agents (63).
EBV-positive Hodgkin’s disease is another candidate for treatment with EBVspecific
CTLs. Five patients who received autologous EBV-specific CTLs in a phase I
study had temporary clinical improvements, including increases in EBV-specific CTL
precursor frequency, reductions in high virus loads, resolution of type B symptoms, and
stabilization of disease (64). Current improvements include the generation of CTL lines
that are specific for the limited range of viral antigens expressed in Reed-Sternberg cells.
Vaccination
The high incidence of nasopharyngeal carcinoma (NPC) in southern China (1–2%
of the general population) has been associated with early infection by EBV (65). A vaccine
that could prevent or delay primary infection with EBV by establishing mucosal
immunity might decrease the incidence of EBV-associated NPC (66). The gp340 envelope
glycoprotein of EBV, the principal target for neutralizing antibodies, binds to the
cellular receptor for the C3d component of complement, enabling virus to enter the
B-cells. A vaccine based on purified gp340 has been shown to reduce the virus load
and protect against EBV-associated LPD in cotton-top tamarins (2). When tested in
Chinese children, live recombinant vaccinia virus engineered to express gp340 induced
EBV-specific immune responses with protection against and/or delay of EBV infection
(67). However, the outcome of this study may not be evident for 40 years.
Because the CTL-mediated immune response is necessary for control of EBV infection,
the possibility of priming T-cells by peptide immunization, before primary infection,
has been raised. One advantage of accelerating the CTL response to primary
infection is that one may be able to limit subsequent colonization of the B-lymphocyte
pool (2). This approach would require peptides that are customized to the patients’
HLA phenotype (17) or perhaps a polytope vaccine, as described previously (45). An
effective vaccine against EBV would be especially useful for seronegative recipients of
solid organs from seropositive donors. Such patients are generally at greater risk of
developing EBV-LPD (68).