Immunotherapy for Infectious Diseases

270 Sili, Heslop, and Rooney
CONCLUSIONS AND FUTURE PERSPECTIVES
Adoptive immunotherapy with antigen-specific CTLs has proved to be safe and
effective in immunosuppressed patients. Our clinical trials have suggested that the prophylactic
use of ex vivo generated CTLs is optimal and provides protection against
virus-associated tumor formation. If CTLs are used therapeutically, attention must
be paid to the potential of a damaging inflammatory response and the emergence of
“antigen-loss variants.” As with any immunotherapeutic strategy, the use of polyclonal
CTL lines targeted to more than one antigen or to antigens that are essential for the
transformed phenotype may preclude the outgrowth of “escape mutants.” Tumors in
patients who are not immunosuppressed will probably be more difficult to treat because
of tumor-mediated immune evasion strategies.
Genetic immunization and vaccination with peptides have also proved to be efficacious
in eliciting specific immune responses. As clinical trials progress, it will be
important to identify the best method of administering these agents. Genetic immunization
with entire protein sequences offers natural processing and presentation of
peptides, precluding the need to determine the immunogenic peptide for the patient’s
HLA type. Among the advantages offered by peptide-based approaches are safety, easier
clinical grade production, and specific induction of immune responses to subdominant
epitopes. The uses of single peptides for vaccination will probably lead to
epitope-loss mutants and should therefore be avoided. Polytope vaccines linking different
CTL epitopes may offer better protection. The optimal strategy is likely to be
disease-dependent. Clearly, the use of dendritic cells for both peptide vaccination and
genetic immunization results in more potent responses.
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