Download File - JOHN J. HADDAD, Ph.D.

Peptide-Based Active Immunotherapy in Cancer 123
PROSPECTS
The growing number of TAA identified in many tumor types becomes a solid
basis for peptide vaccine development. However, the antigenic profile of human
tumors is very complex and consists of many peptides originating from various
classes of protein. This fact should be considered carefully in designing anticancer
vaccines. An important question is which tumor antigens are the most important in
tumor regression in vivo. In any case, the ideal peptide vaccine most likely will
consist of a cocktail of tumor antigenic peptides. However, the number of epitopes
in the vaccine cocktail should be evaluated carefully since CTL responses in AIDS
patients directed to fewer epitopes are associated with better clinical outcome (89).
In this case it appears that the stimulation of multiple simultaneous CTL responses
is clinically inefficient. The dose of antigen and the speed of antigen release in the
vaccine formulations are also very important. High doses of antigen released faster
may induce T-cell tolerance (90). Immune tolerance may be due to fast expansion
and subsequent elimination of specific T-cell clones, or to apoptosis induced by
repeated stimulation of already stimulated T-cells in cell cycle (91,92). Therefore,
it is essential to select as immunogens those epitopes against which tolerance has
not been induced (93,94).
Currently, clinical responses to peptide vaccines, as determined by the criteria
set for chemotherapy and radiation, have been difficult to assess. However,
the lack of toxicity of peptide vaccines in patients with many different tumor
types, and the clearly observed efficacy in some studies, support the use of peptide
vaccination. Future peptide vaccine strategies will most likely focus on more
potent and combined approaches for immunization. Applied in conjunction with
surgery, radiotherapy, and/or chemotherapy, peptide vaccines can be effective in
eliminating micro-metastases, in decreasing the immunosuppressive effects of the
chemotherapy or radiotherapy, and in increasing the resistance to viral or bacterial
infections frequently occurring in cancer patients. Recent advances in the design of
polyvalent vaccines targeting several antigens are also very promising. In addition,
the possibility to treat patients with peptide vaccines earlier in the course of the
disease and to combine vaccines with other treatment modalities may also improve
the vaccine efficacy. As a result, immunotherapy with peptide vaccines may
become a major treatment modality of cancer in the near future.
REFERENCES
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3. Yewdell JW, Norbury CC, Bennink JR. Mechanisms of exogenous antigen presentation
by MHC class I molecules in vitro and in vivo: implications for generating
CD8þ T cell responses to infectious agents, tumors, transplants, and vaccines. Adv
Immunol 1999; 73:1–77.