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

Peptide-Based Active Immunotherapy in Cancer 121
were emulsified with IFA and administered with SD-9427 (progenipoietin)—an
agonist of granulocyte colony-stimulating factor and the FLT-3 receptor (80).
This study found that the SD-9427 combined with a multipeptide vaccine was
generally well tolerated, and that the majority of patients with resected melanoma
mounted an antigen-specific immune response against the multipeptide
vaccine. Butterfield et al. studied the induction of T-cell responses to HLA-
A*0201 immunodominant peptides derived from alpha-fetoprotein (AFP) in
patients with hepatocellular cancer (81). In this study the authors tested the
immunologic paradigm that high concentrations of soluble protein contribute to
the maintenance of peripheral tolerance/ignorance to self-protein. They confirmed
that the patients’ T-cell repertoire was capable of recognizing AFP in the
context of MHC class I even in an environment of high circulating levels of this
oncofetal protein. Our group identified two HLA-A2-restricted peptides derived
from hTRT, and induced hTRT-specific CTL in vitro (19). More important, we
also demonstrated that the hTRT-specific CTL lysed a variety of HLA-A2positive
cancer cell lines, but not HLA-A2-negative cancer cell lines. All of
these cancer cell lines were hTRT positive as determined by the TRAPeze assay
(Intergen). A phase I clinical trial was performed by Vonderheide et al. to
evaluate the clinical and immunologic impact of vaccinating advanced cancer
patients with the HLA-A2-restricted hTRT I540 peptide presented with keyholelimpethemocyaninbyexvivogeneratedautologousdendriticcells(82).It
was found that hTRT-specific T lymphocytes were induced in four of seven
patients with advanced breast or prostate carcinoma after vaccination with
dendritic cells pulsed with hTRT peptide. It is important to note that no significant
toxicity was observed despite concerns of telomerase activity in rare
normal cells. These results demonstrated the immunologic feasibility of vaccinating
patients against telomerase and provided rationale for targeting selfantigens
with critical roles in oncogenesis. An interesting study utilized the flt3
ligand as a systemic vaccine adjuvant with the E75 HLA-A2 epitope from
HER-2/neu (83). Twenty patients with advanced-stage prostate cancer were
enrolled in this study. Dendritic cells were markedly increased in the peripheral
blood of subjects receiving flt3 ligand with each repetitive cycle, but augmentation
of antigen-presenting cells within the dermis was not observed. No
significant peptide-specific T-cell responses were detected. The authors concluded
that the inability of fit3 ligand to augment the number of peripheral skin
antigen-presenting cells may have contributed to the absence of robust peptidespecific
immunity detectable in the peripheral blood of immunized subjects
treated with flt3 ligand. Recently, Hueman et al. performed clinical trials in
breast cancer patients to test the HER2/neu peptide vaccine (E75) (84,85).
Blood samples from 22 healthy individuals and 22 patients, including pre- and
post-vaccination samples from seven vaccinated HLA-A2þ patients, were
obtained. Vaccination with E75 resulted in CD4þ T cell recruitment and was
associated with a significant decrease in circulating regulatory T cells and
TGF-beta levels in the majority of the vaccinated patients. These results