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Generex Biotechnology, and their wholly owned subsidiary Antigen Express, are developing promising new drugs to treat diabetes, as well as synthetic peptide vaccines targeting HER2/neu cancer and pandemic flu. The flagship product for Generex is Oral-lyn buccal insulin. Antigen Express' leading vaccine is the AE37 HER2/neu synthetic peptide vaccine to prevent breast cancer recurrence. I am not qualified to offer investment or medical advice, and make no claims that I am an expert in these areas. I am a layman and a shareholder in this company. The left side of Pipeline Review holds blogs regarding Generex and Antigen Express, while the right side offers items of due diligence mixed with my analysis which may be of interest to others seeking to learn about Generex's pipeline. If the left side only shows the latest blog, click on the word home to view them all.

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Monday, February 21, 2011

Putting My Experiences Watching Quincy, M.E. to Good Use, While Reading the Latest Peer Review Related to Generex's AE37 Vaccine

Sometimes, we have to amuse ourselves, and laugh at the absurd. As the stock for my favorite biotech continues to falter, I'll try and accomplish both, by making a futile attempt to analyze that latest peer review that includes data from Generex (GNBT) Biotechnology's AE37 HER2/neu Ii-Key peptide based vaccine. Researchers from the United States Military Cancer Institute have authored a new report, titled "Comparison of Different HER2/neu Vaccines in Adjuvant Breast Cancer Trials: Implications for Dosing of Peptide Vaccines", that appears in the February 2011 edition of Expert Review of Vaccines.

As I've noted before, the USMCI has conducted multiple adjuvant clinical trials using immunogenic peptides from the HER2/neu protein [AE37/E75/GP2] plus GM-CSF given intradermally to breast cancer patients. Adjuvant therapy for breast cancer is any treatment given after primary therapy to increase the chance of long-term survival. Researchers have surmised that peptide based cancer vaccines may have limited clinical tumor response in metastatic cancer, meaning cancer that has spread to other parts of the body, so the USMCI has chosen to study peptide based vaccines in the adjuvant setting.

I hope I am not being overly simplistic, I barely understand all of this myself. Last fall, Col George Peoples, the Director & Principal Investigator of the Cancer Vaccine Development Program, and the Deputy Director of the USMCI, explained to me in an email exchange that "all the data that we have indicates that vaccines are most effective at a point when the immune system can get a handle on the cancer before it gets too aggressive and less recognizable to the immune system". The latest report, of which he is the main author, represents their first attempt to compare all three of the HER2/neu peptide vaccines tested in their clinical trials, with an emphasis on the dosing strategy needed to gain the greatest clinical benefit. At least, I think, so you can buy the report here to decide for yourself.

The publicly available abstract reads:

We have performed multiple adjuvant clinical trials using immunogenic peptides from the HER2/neu protein (AE37/E75/GP2) plus (GM-CSF) given intradermally to breast cancer patients. Four trials were performed with similar dose-escalation design with increasing doses of peptide (AE37/E75/GP2) and varying amounts of GM-CSF. Dose reductions (DRs) were made for significant local and/or systemic toxicity by decreasing GM-CSF for subsequent inoculations. Ex vivo and in vivo immunologic responses were used to compare groups. Of 132 patients, 39 required DR (30 for robust local reactions [DR-L]). DR patients, particularly DR-L, had greater immune responses both ex vivo and in vivo. Postvaccine delayed-type hypersensitivity in DR-L patients compared with all others was larger for E75 (p = 0.001), AE37 (p = 0.077) and GP2 (p = 0.076). All three peptide vaccines were safe and well-tolerated. These findings have led to a clinically relevant optimal vaccine dosing strategy, which may be applicable to other peptide-based cancer vaccines.

The report highlights the dose-escalation trial results for the three HER2/neu derived peptides that have been studied in their clinical trials. For AE37, owned by our own Generex Biotechnology, the report includes data from the Phase I study in early stage breast cancer patients that was completed a couple of years ago. I know, we want Phase II data, but take this for now. The same type of study is included for GP2, while data available for E75 included completed Phase I and Phase II results. E75 has been studied far longer than AE37 or GP2, and this vaccine is licensed to Apthera, Inc. At this point, I am only interested in AE37, and admittedly for selfish reasons. The AE37 Phase I study included 15 disease-free, node negative breast cancer patients, 60% of whom required dose reduction for robust local reactions. AE37 is coupled with the Ii-Key modification, which I believe increases its potency as compared to GP2 and E75.

When I first noticed the p values in the abstract, showing that post vaccine delayed-type hypersensitivity, or DTH, in DR-L patients was larger for E75 than AE37 or GP2, I thought they were finding increased potency in that particular peptide vaccine, which isn't coupled with the Ii-Key. Evidently, they are looking specifically at DR-L patients, or 30 of 139 patients, when making that analysis. The goal is to create personalized, or tailored, vaccines. All of these sub groups become important, as dosing plays a key part of their approach. As long as they understand what that means, we are in good shape, since I get a little lost in the scientific jargon.

The researchers explain that the three peptides studied in their trials are similar, but have unique differences. AE37 is the most individual, as it is a HLA class II-binding peptide, stimulating CD4 T-helper cells, and appears generate longer term specific immune responses as compared to the others. GP2 and E75 are HLA class I restricted, that stimulate CD8+ T-helper Cells, while AE37 is a promiscuous peptide allowing for a broader relevancy. I have noted that difference in previous blogs. The researchers remark that HLA-A2+/HLA-A3+ patients, or those that GP2 and E75 are restricted to, make up 60–75% of the population. AE37, the promiscuous peptide, can benefit them all. I should say potentially, but my shares in GNBT forced me to leave that word out of the sentence. I apologize, the beaten down shares get a little promiscuous as well.

The report states that DTH testing has been described as a very reliable method of monitoring immune response to cancer vaccines. It was work by Dr Mary Disis, from the Tumor Vaccine Group at the University of Washington, whose research I have also studied, that found DTH responses correlate with better antigen-specific T-cell responses and reflect systemic immunization. That thought brings the USMCI researchers to consider whether large DTH reaction correlate with clinical outcome. They looked at their E75 data, which as I informed is more expansive due to the longer duration of study, to find that greater post vaccine DTH reactions were associated with decreased recurrence and mortality. This why the abstract contains data specific for 30 of 139 patients, since they represent those requiring dose reductions due to larger local reactions.

The USMCI concludes the report with their optimal method of dosing for the HER2/neu peptide vaccines under their care, which they believe are relevant to other peptide based vaccines. Their data shows that AE37's enhanced potency is demonstrated by the largest DTH reaction produced in their overall analysis of the three peptide vaccines. DTH reactions reveal that AE37 is greater than GP2, which is greater than E75, for both DR and NDR patients. I'm not sure what it means, but I think this shows AE37 is the greatest, at least in providing DTH reactions, which may correlate with positive clinical outcome.

The ultimate goal of the USMCI is to develop a "combinational multiple epitope breast cancer vaccine with broad patient applicability to be given to disease-free patients with the aim to prevent recurrences and decrease breast cancer mortality". Since GP2 and E75 are HLA class I restricted, I imagine that any truly potent and long lasting multi-epitope vaccine would require the promiscuous AE37 Ii-Key Hybrid. The authors of the study didn't necessarily conclude that, I did, although my science experience is limited to watching Quincy, ME.

I'm not sure if that counts. I'm certain I've only succeeded in being absurd. The science points towards a bright future, even if the current day is cold and stormy. I'll take that thought to heart as we await meaningful news from the good folks at Generex, and hope it comes soon. GNBT shares could use a dose of enhanced potency.