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Peptide-Based Active Immunotherapy in Cancer 117
vaccination. Serial administrations of this peptide appeared to boost the level of
cytotoxicity in vitro, although clinical regression of the tumor was not observed.
Peptides derived from NY-ESO-1, one of the most immunogenic tumor antigens,
were used to immunize 12 patients with metastatic NY-ESO-1 expressing cancers,
including melanoma (53). This trial demonstrated induction of primary NY-
ESO-1-specific CTL responses as well as stabilization of disease and regression
of individual metastases in three patients. In another trial, patients with advanced
pancreatic carcinoma were vaccinated with a synthetic ras peptide pulsed on
antigen-presenting cells isolated from peripheral blood (54). This procedure led
to generation of cancer cell–specific cellular response, without side effects.
However, in all patients, tumor progression was observed after the vaccination.
Based on promising preclinical results, Celis et al. conducted a clinical trial
using the MPS160 vaccine in patients with metastatic melanoma. MPS160 is a
gp 100–derived melanoma peptide that contains overlapping HLA-A2–, DR53-,
and DQw6-restricted T-cell epitopes. It was found that none of the 28 patients
exhibited objective tumor responses or severe toxicities, and that four of the 28
patients remained progression free for over 100 days. Based on immunologic
analysis for 21 patients, it was determined that vaccination increased the frequency
of vaccine-specific, nonfunctional CTL in 10 patients, and there was
evidence of systemic cytokine/immune dysfunction (55). Noguchi et al. recently
performed two well-designed clinical trials with prostate cancer patients. In the
first trial the safety and immune responses to a personalized peptide vaccine
were evaluated in preoperative prostate cancer (56). Ten HLA-A24þ patients
with localized prostate cancer received the peptide vaccine weekly, and soon
after vaccination, a retropubic radical prostatectomy was performed. It was
found that the peptide vaccination was safe and well tolerated with no major side
effects. In eight out of the 10 patients, increased CTL response and anti-peptide
IgG titer was observed. CD8þ T cell infiltration was also increased at the tumor
site. In the second study, the prognostic factors of patients with metastatic
hormone refractory prostate cancer (HRPC) were studied. Fifty-eight patients
with metastatic HRPC received a combination therapy of personalized peptide
vaccination and low-dose estramustine phosphate (57). Results showed that there
were no major side effects and that this vaccine was also well tolerated. In 27 of
37 patients, increased levels of CTL precursors were found, and in 36 of 41
patients, increased IgG responses were observed. Also, a prostate-specific antigen
decline of at least 50% occurred in 24% of patients.
OPTIMIZING PEPTIDE-BASED VACCINES
Several strategies for modifying peptides have been attempted to improve their
efficiency as cancer vaccines. The clinical use of peptides is limited by their
rapid proteolytic digestion. To overcome this limitation, Celis et al. designed a
peptide construct containing a pan-reactive DR epitope, a CTL epitope, and a
fatty-acid moiety (58). A lipopeptide-based therapeutic vaccine was able to
induce strong CTL responses both in humans and in animals (59). Several studies