[Lani]

cancer cells from the immune system ...or perhaps as the paper speculates


Discussion
HER2/neu is a source of immunogenic peptides and is
expressed in >75% of breast cancer patients. This protein is
overexpressed in 25% of breast cancer, and these patients are
candidates for trastuzumab immunotherapy. In a phase II
clinical trial investigating the use of E75 as a preventive vaccine
in high-risk breast cancer patients, our group has previously
shown the vaccine to be safe, effective in eliciting an immune
response, and clinically efficacious with decreased recurrence
rates after a median follow-up of 20 months; however, this
clinical benefit was lost because immunity waned without
booster inoculations (23, 31).
In this article, we have shown that patients with all levels of
HER2/neu expressi on as determi ned by IHC and FISH
responded immunologically to E75 vaccination. Importantly,
In the
low-expressor groups, we found that the vaccinated patients
had a 41.2% reduction in recurrences and 100% reduction in
mortality. This benefit highlights the difference in mechanism
between the E75 peptide vaccine and trastuzumab. The latter,
trastuzumab, has been shown to be less effective in low-
expressor patients and is not indicated for use in this group,
whereas the vaccine only requires protein expression, not
overexpression (14). In fact, the immunologic data would
suggest that low-expressor patients respond better to the
vaccine than overexpressor patients, suggesting an element of
immunologic tolerance in the overexpressor patients.
Many of the patients in this study, regardless of IHC status, had
some element of pre-existing immunity as evident by prevaccine
E75-specific CD8+ T-cells levels of >0.3%. Even the antigen-naBve
patients (IHC 0) had on average 0.5% F 0.1% E75-specific CD8+
T cells, with five of the seven antigen-naBve vaccinated patients
expressing pre-existing immunity (>0.3%). There are several
possible explanations for this pre-existing immunity in purport-
ed antigen naBve patients. One possibility is that the IHC
assessment was inaccurate because this assay is somewhat
subjective or could have failed to provide a complete evaluation
of the tumor specimens. Alternatively, the explanation may be
immunoediting, the process of elimination, equilibrium, and
escape described by Dunn and colleagues (32). Elimination, also
known as cancer immunosurveillance, is responsible for destroy-
ing transformed cells; equilibrium occurs when new population
of tumors cells with increasing mutations are present; escape is
when tumor growth continues unrestrained by the immune
system. This process suggests that HER2-positive tumors cells
might have been eliminated. Evidence of ongoing immunosur-
veillance is also suggested in our study on healthy volunteers that
showed rapidly inducible E75-specific cytotoxic T lymphocytes
in 20% of healthy volunteers (33). In our previous trials, we have
assumed that the peptide vaccine was amplifying a pre-existing
immunologic response; however, in the case of truly antigen-
naBve patients, the vaccine may be required to induce a response
de novo . Ultimately, this is a crucial concept for the further
investigation of E75 as a truly preventive vaccine in patients at
high risk for first-occurrence breast cancer.