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Peptide-Based Active Immunotherapy in Cancer 111
others (11,21). In breast cancer and other adenocarcinomas, a polymorphic
epithelial mucin (22) and HER2/neu proto-oncogene (23) have been characterized
as tumor antigens.
Promising novel approaches for identification of TAA have been developed
recently. Applying a combination of techniques, such as “suppression
subtractive hybridization” and “transmembrane trapping,” Di Cristina et al.
identified a large panel of cDNA fragments encoding a variety of TAA, representing
novel tumor-specific targets (24). Furukawa et al. studied the roles of
ganglioside GD3 in human malignant melanomas and those of GD2 in small cell
lung cancer as modulators of the malignant properties of cancer, suggesting their
function as novel targets for cancer therapy (25). Recently, it was found that
regulator of G-protein signaling 5 (RGS5) is broadly unregulated in a wide
variety of malignant cells and that RGS5-specific CTL lines possess antigenspecific
and HLA-restricted cytolytic activity against tumor cells (26). Newly
identified TAA-derived peptides also demonstrated a strong potential to be
particularly useful in the treatment of hematologic malignancies (27,28).
In contrast to class I TAA, little attention has been paid to the identification
of class II TAA, mostly because of the difficulties in their identification. However,
a growing number of studies confirm the important role of CD4þ Tcellsin
controlling tumor growth (29). Several important studies on cancer patients
demonstrated the essential role of the CD4þ T cells for optimal CTL induction
(30,31). Klyushnenkova et al. were able to successfully stimulate CD4þ T lymphocytes
from HLA-DRB1*1501-positive donors, with prostatic acid phosphatase–derived
class II–restricted peptides showing their potential as a new target for
peptide-based immunotherapy (32). These findings confirm that tumor-specific
CD4þ T lymphocytes are required for optimal induction of CTL against the
autologous tumors. Therefore, both class I and class II peptides should be used to
optimize the therapeutic effect of the peptide-based cancer vaccines.
PRECLINICAL AND CLINICAL STUDIES
The identification of peptide sequences recognized by CTL has led to attempts to
directly induce CTL responses in vivo (33,34). Successful immunization of mice
has been accomplished with peptides formulated with immunostimulating
complex (35), entrapped in liposomes (36), encapsulated in microspheres (37),
and osmotically loaded into syngeneic splenocytes (38) or coated on their surface
(39). Effective immune responses were also elicited in mice with a mutant p53
peptide in adjuvant (40), or with either mutant or wild-type p53 peptides loaded
on dendritic cells (41). We showed in two murine antigenic systems that fusion
peptides with a synthetic ER signal sequence at the NH2-terminus of the minimal
peptide were more effective than the minimal peptide alone in generating specific
CTL responses (42). Furthermore, we found that the CTL response was
MHC class II independent, could not be attributed to increased hydrophobicity
of the fusion peptides, and was very effective in prolonging the survival of