[Cynthia]

Friends,

It has been a long time since I last posted. I do, however, continue to follow the discussions and offer my thoughts and prayers to all in our community.

As a graduate of the E75 trial (and its booster program), I would like to weigh in on this discussion. While I certainly am not endorsing any trial or encouraging anyone to participate in anything, I want to make sure that trials are being fairly considered. I would hate to see a potentially promising trial rejected out-of-hand before it is thoroughly and accurately vetted (recognizing of course the inherent uncertainty of any trial.)

First, the trial referenced by alicem in her initial post is the current phase II trial of two newer HER2-derived peptides (GP2 and AE37). I believe that Becky is referring to the E75 peptide trial, and not the GP2 or AE37 peptides. (More about the E75 trial later.)

Second, I understand that the criteria for inclusion in the E75 trial, and other than HLA specificity, disease-free status, and immunologically competent (reactive skin testing), was as inclusive as could be. I disagree with the notion that patients were being cherry picked for inclusion.

Third, regarding the statements about HER2 expression in the heart, please see below….

Breast Cancer Res Treat. 2003 Nov;82(1):23-8.

Analysis of HER2 and HER4 in human myocardium to clarify the cardiotoxicity of trastuzumab (Herceptin).
Fuchs IB, Landt S, Bueler H, Kuehl U, Coupland S, Kleine-Tebbe A, Lichtenegger W, Schaller G.
Department of Gynecology, Frauenklinik, Charité Campus Virchow Clinic, Berlin, Germany. ilka.fuchs@charite.de

PURPOSE: When combined with anthracyclines, the humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) provides significant clinical benefit for women with HER2-overexpressing metastatic breast cancer. However, its use is limited by severe cardiotoxicity. To clarify whether myocardial HER2 and HER4 expression in response to anthracycline exposure and cardiac damage contributes to cardiotoxicity, we assessed expression of HER2 and HER4 in pathologically altered myocardium. EXPERIMENTAL DESIGN: Cardiac biopsies from 60 patients with severe heart disease and cardiac tissue from 35 patients with breast cancer were obtained. Twenty-five of the patients with breast cancer had previously received anthracyclines. Three of 10 anthracycline-naïve patients with breast cancer had received trastuzumab. Expression of HER2 and HER4 was analyzed immunohistochemically (HER2: HercepTest/A0485 (Dako), Cy3 detection (Dianova); HER4: Ab-4 (NeoMarkers)). FISH analysis (Ventana) was used to assess HER2 gene amplification. RESULTS: Immunohistochemistry revealed weak HER2 membrane staining in six cardiac biopsies, appearing as dotted staining of the whole cell membrane and intensified HER2 signal using fluorescent Cy3 labeling. No HER2 membrane staining was detected in the remaining 54 cardiac biopsies or in the myocardium of the 35 patients with breast cancer. HER2 gene amplification was not observed. All specimens showed the mild cytoplasmatic HER4 staining of normal myocardium. No strong HER4 expression was detected. CONCLUSIONS: Cardiac alterations are not associated with an strong increase in HER2 and HER4 levels. IHC detects potential low-level HER2 expression in some samples. However, a more sensitive technique may be needed for studies of the role of HER2 in cardiac tissue. These data do not exclude a role for inhibition of cardiac HER2 expression by trastuzumab in the onset of heart failure in trastuzumab-treated patients.

In this study, minimal amounts of HER2 was detected in 6 out 95 cardiac biopsies (60 with severe heart disease and 35 breast cancer patients). No one is completely sure why Herceptin is cardiotoxic but it’s not because of HER2 expression in the heart. In fact, it is very difficult to find detectable levels of HER2 in any human adult tissue except for cancers. That’s why most vaccines target it. Thus far, no cardiac toxicity has been seen any of the HER2 vaccine trials (Disis).

Finally, the FDA has completed its review of the E75 phase II data and the proposed phase III trial design and has approved the manufacturer's (Apthera’s) SPA (special protocol assessment). Please see the following:

Apthera Secures SPA for Pivotal
NeuVax Trial in Breast Cancer
By Jennifer Boggs

Assistant Managing Editor

After quietly chugging along amid a swirl of cancer vaccine
news, privately held Apthera Inc. popped up on the radar,
armed with a special protocol assessment for a pivotal
Phase III trial of its peptide-based immunotherapeutic,
NeuVax, in early stage breast cancer patients.
The news came only days after fellow cancer vaccine
firm Oncothyreon Inc., of Seattle, reported that Stimuvax
partner Merck KGaA decided to add a Phase III breast cancer
study to its ongoing Phase III study in non-small-celllung
cancer, signaling a re-energized interest in the space
that had been rife with disappointment prior to Dendreon
Corp.’s Phase III success with Provenge (sipuleucel-T) in
prostate cancer.

Apthera’s SPA, finalized after a 21-month process with
the FDA, calls for a single, Phase III trial enrolling 700
women diagnosed with HER2/neu-expressing tumors who
have completed standard-of-care treatment – surgery,
chemotherapy and radiotherapy. Patients also must have a
common HLA haplotype, specifically HLA-A2 or -A3.
The primary endpoint will be disease-free survival,
with the first analysis of data expected to occur after 70
recurrence events, or about three years after the start of
the trial.

The Scottsdale, Ariz.-based firm did not provide a start
date for the study. Nor did it disclose whether it intends to
fund the trial itself or seek a partner to help offset the costs.
Apthera executives could not be reached for further comment,
though Alton C. Morgan, president and CEO, said in a
statement that the SPA “created a value inflection milestone
for both the product and the company.”

Apthera has kept much of its financing private to date,
though earlier this month it licensed commercial rights to
NeuVax in South Korea to Kwang Dong Pharmaceutical Co.
Ltd. in exchange for milestone payments, royalties on product
sales, an undisclosed equity investment and a pledge
from Kwang Dong to invest in a future round of financing.
Founded in 2005 with technology licensed from the
University of Texas M.D. Anderson Cancer Center in Houston,
and the Henry M. Jackson Foundation for the
Advancement of Military Medicine Inc. in Rockville, Md.,
Apthera’s focus centers on a pipeline of peptide-based
immunotherapies.

As the most advanced of those, NeuVax is designed
with the E75 peptide, a rare T-cell peptide believed to boost
pre-existing anticancer immunity, and initially is aimed at
the subset of HER2-positive breast cancer patients who do
not qualify for treatment with Herceptin (trastuzumab,
Genentech).

Earlier in the pipeline, Apthera is working on NeuVax in
prostate cancer. The firm recently reported promising data
from HER2-positive patients at high risk for recurrence at
the American Society of Clinical Oncology meeting in
Chicago, showing that the median time to disease recurrence
from prostatectomy was 14 months for the NeuVax
group vs. 8.5 months for the control group. Data also
showed that patients with stable prostate-specific antigen
throughout treatment exhibited a median time to recurrence
of 42.7 months. ■

Just my two cents.

Stay well.