the latest on the E75 vaccine

[Lani]

Clin Cancer Res. 2009 Apr 7. [Epub ahead of print]
The Impact of HER2/neu Expression Level on Response to the E75 Vaccine: From U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

Benavides LC, Gates JD, Carmichael MG, Patel R, Holmes JP, Hueman MT, Mittendorf EA, Craig D, Stojadinovic A, Ponniah S, Peoples GE.
Authors' Affiliations: Department of Surgery, General Surgery Service, Brooke Army Medical Center, Houston, Texas; Department of Medicine, Hematology and Medical Oncology Service, and Department of Surgery, General Surgery Service, Walter Reed Army Medical Center, Washington, District of Columbia, Joyce Murtha Breast Care Center, Windber Medical Center, Windber, Pennsylvania, Department of Hematology and Medical Oncology, Naval Medical Center San Diego, San Diego, California, Cancer Vaccine Development Program, U.S. Military Cancer Institute, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
PURPOSE: HER2/neu, a source of immunogenic peptides, is expressed in >75% of breast cancer patients. We have conducted clinical trials with the HER2/neu E75 peptide vaccine in breast cancer patients with varying levels of HER2/neu expression. Vaccine response based on HER2/neu expression level was analyzed.EXPERIMENTAL DESIGN: Patients were stratified by HER2/neu expression. Low expressors (n = 100) were defined as HER2/neu immunohistochemistry (IHC) 1(+) to 2(+) or fluorescence in situ hybridization < 2.0. Overexpressors (n = 51) were defined as IHC 3(+) or fluorescence in situ hybridization >/= 2.0. Additional analyses were done stratifying by IHC status (0-3(+)). Standard clinocopathlogic factors, immunologic response (in vivo delayed-type hypersensitivity reactions; ex vivo human leukocyte antigen A2:immunoglobulin G dimer assay), and clinical responses (recurrence; mortality) were assessed.RESULTS: Low-expressor (control, 44; vaccinated, 56) versus overexpressor patients (control, 22; vaccinated, 29) were assessed. Low expressors, overexpressors, and most IHC-status vaccinated groups responded immunologically. Vaccinated low-expressor patients had larger maximum immunologic responses compared with overexpressor patients (P = 0.04), and vaccinated IHC 1(+) patients had increased long-term immune response (P = 0.08). More importantly, compared with controls, low-expressor patients had a mortality reduction (P = 0.08). The largest decrease in mortality was seen in IHC 1(+) patients (P = 0.05). In addition, a subset of overexpressor patients (n = 7) received trastuzumab before vaccination, and this combination seems safe and immunologically beneficial.CONCLUSIONS: Most patients with various levels of HER2/neu expression responded immunologically and seemed to benefit from vaccination. The low expressors, specifically IHC 1(+) patients, had more robust immunologic responses and may derive the greatest clinical benefit from the E75 vaccine.
PMID: 19351776

[Ellie F]

Thanks again Lani for such encouraging information. It feel like they are on the right track with vaccines.The other good news seems to be that herceptin is helpful when given with it and also safe.
Got a little confused about the best responders (IHC+1)can you explain what this means in relation to her2?.
Many thanks Ellie

[hutchibk]

Just wondering if there are there any vaccine trials that those of us mets kids who are otherwise "heavily pre-treated" can qualify for? Especially if we remain in ongoing treatment?

[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.

[Rich66]

Yeah...could this have use amongst metsters? MOm is her2 borderline so I am especially interested