Antigen Express's AE37 Vaccine at ASCO 2013

Abstracts for the American Society of Clinical Oncology (ASCO) Annual Meeting were released today at 6 pm, ahead of the meeting which will be held May 31 - June 4, 2013 in Chicago, Illinois. Two abstracts featuring AE37 were accepted for poster publication, whith another published in conjunction with the 2013 Annual Meeting, but not presented at the Meeting. While none of the abstracts contain pivotal data, they do illustrate positive trends from studies of AE37 in breast and prostate cancer patients.

Here are the abstracts:

Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study. Abstract No: 3095

Author(s): Eleftheria A Anastasopoulou, Efi Pappou, Panagiotis Tzonis, Alexandros Ardavanis, Sathibalan Ponniah, Constantin N. Baxevanis, James L. Murray, Michael Papamichail, Sonia A. Perez, George Earl Peoples, Elizabeth Ann Mittendorf; Cancer Immunology and Immunotherapy Center Saint Savas Cancer Hospital, Athens, Greece; Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece; Cancer Vaccine Development Program, United States Military Cancer Institute, USUHS, Bethesda, MD; The University of Texas MD Anderson Cancer Center, Houston, TX; Cancer Immunology and Immunotherapy Center, Athens, Greece; San Antonio Military Medical Center, San Antonio, TX

Background: We are conducting a multicenter randomized phase II trial of AE37, the Ii-Key hybrid peptide of HER2 776-790 (AE36). The purpose of the study is to determine if the AE37 vaccine can prevent recurrence in disease-free conventionally treated node-positive (NP) and high-risk node-negative (NN) breast cancer patients at significant risk for recurrence. Since clinical efficacy is anticipated to occur as the result of long lasting memory immune responses induced by vaccination, repeated booster inoculations were scheduled as part of the trial. Here we present data on immune responses in patients who received boosters up to 24 months after completion of the primary vaccination series (PVS).

Methods: The trial is enrolling NP or high-risk NN patients with any degree of HER2 expression (IHC 1-3+ or FISH > 1.2) rendered disease-free following standard of care therapy. The vaccine group (VG) received AE37+GM-CSF and control group (CG) GM-CSF alone in 6 monthly i.d. inoculations followed by boosters administered every 6 months x 4. Immunologic responses were assessed in vivo by dermal reactions at the inoculation site, and in vitro, against the AE36 peptide, with proliferation and IFN-γ ELISPOT assays.

Results: 25 patients in the VG and 23 in the CG have completed their boosters. After the last booster (BRC24), 100%, 54% and 54% in the VG (vs. 9%, 18% and 27% in the CG) responded by dermal reaction, proliferation and IFN-γ ELISPOT, respectively. Mean dermal reactions (orthogonal mean in mm) in vaccinated patients was 25.9±3.13 at completion of the PVS (R6) and increased to 35.47±4.35 at BRC24 (p=0.01). VG patients increased their proliferation response (stimulation index, SI) to AE36 from 0.97±0.046 at baseline (R0) before vaccination to 2.27±0.57 at R6 (p=0.0003) which was maintained until BRC24 (SI 2.21±0,33, p<0.0001). The number of IFN-γ specific spots/106 PBMC increased from 26.88±12.36 at R0 to 40.35±17.02 (p=0.07) at R6, up to 62±16.82 (p=0.0076) at BRC24. Conclusions: Our data demonstrate that AE37 vaccine boosters enhance the immune responses against HER elicited during the PVS, thus sustaining long lasting immunity, a prerequisite for possible clinical efficacy which is currently being evaluated.

Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence Abstract No: 3097

Author(s): Alfred F Trappey, John S. Berry, Timothy J Vreeland, Diane F. Hale, Alan K. Sears, Sathibalan Ponniah, Sonia A. Perez, Guy T. Clifton, Michael Papamichail, Nathan M. Shumway, Elizabeth Ann Mittendorf, George Earl Peoples; Brooke Army Medical Center, San Antonio, TX; Cancer Vaccine Development Program, United States Military Cancer Institute, USUHS, Bethesda, MD; Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece; Cancer Immunology and Immunotherapy Center, Athens, Greece; San Antonio Military Medical Center, Fort Sam Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Surgery, Brooke Army Medical Center, Fort Sam Houston, TX

Background: We are monitoring the incidence of delayed urticarial reactions (DURs) in our phase II trial evaluating adjuvant HER2-specific vaccines (AE37 and GP2) for the prevention of breast cancer recurrence. Here, we characterize DURs and analyze risk factors for their development.

Methods: After completion of standard of care therapy, disease-free node-positive or high-risk node-negative patients (pts) were randomized to receive either a peptide+GM-CSF (VG) or GM-CSF (CG). Pts receive 6 monthly intradermal inoculations during the primary vaccine series (PVS) then four boosters (B) every 6 mos. Immune response is measured by delayed type hypersensitivity (DTH) pre- (R0) and post-PVS (R6) and local reaction (LR) at R1 – R6.

Results: Twenty-four (6.1%) of 393 initiated patients report a DUR; 13 VG (vDUR), and 11 CG (cDUR); vDUR - 9 AE37, 4 GP2. Time to onset of symptoms is 9±5 days (d) and is similar in vDUR/cDUR (p = 0.27). DURs manifest as hives/pruritis in all patients. Average duration of symptoms is 32.6 d ± 8.8 d (no difference in vDUR/cDUR [p = 0.23]). Episodes have resolved with antihistamines or IV/oral steroids. Ten (4 cDUR, 6 vDUR) patients have had recurrent episodes that have resolved similarly. 75% of first episodes occur between R6-B3. For DUR patients v. those who have not had a DUR (noDUR), there are no differences in demographics. DTH response is similar in vDUR pts v. noDUR VG pts (R0- p = 0.34; R6- p=0.40). cDUR pts had a greater DTH response v. CG noDUR pts at R6 (13.2 v 4.7 mm, p=0.01). LRs are greater in DUR pts compared to noDUR pts after the second vaccination (R2 – 66.2 v 48.2 mm, p=0.02). LR for DUR pts decrease and are less than noDUR at R6 (45.4 v 57.4 mm, p=0.09). Relative risk for developing DUR for LR > 100 mm at R2 is 3.49 (1.58-7.68, 95% CI [p=0.004]). At 29.9 months median follow-up, there have been no recurrences in VG and CG DUR v. 75.9% DFS for noDUR (p=0.05).

Conclusions: DURs occur infrequently and without long-term sequelae. Pts at risk for developing DUR are identified early in the vaccine series using LR. Robust immune response in DUR may explain the survival benefit demonstrated here.

The following is the publish only abstract:

Effect of immunization with Ii-key modified HER2 (776-790) peptide vaccine (AE37) on immunologic responses in prostate cancer patients.

Author(s): Sonia A. Perez, Eleftheria Anastasopoulou, Efi Pappou, Panagiotis Tzonis, Stratos Bisias, Anastasios Thanos, Eric von Hofe, Michael Papamichail, Constantin N. Baxevanis; Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece; Antigen Express, Worcester, MA

Background: We have shown that the AE37 vaccine (Ii-Key modified HER2(776-790) peptide) is safe and induces HER2/neu–specific cellular immune responses in patients with prostate cancer (Perez SA et al Clin. Cancer Res. 2010, 16:3495). We now present data from 4-year immunological assessments of prostate cancer patients who received AE37.

Methods: Seventeen patients in a phase I study were given 6 doses of AE37 at monthly intervals and one additional dose a year after initiating treatment. Immunological testing to assess active versus suppressive immunity was conducted one month (intermediate-term immunomonitoring [ITI]) and 3 years (long-term immunomonitoring [LTI]) after the final dose of AE37. ELISPOT and proliferation assays were conducted to assess cytokine secretion and mitogenic response to antigen. DTH reactions were measured to assess in vivo immune response to antigen. All assays were conducted using native HER2(776-790) peptide (AE36). The percent Treg cells and ng/ml TGFβ were determined as markers for immune suppression.

Results: Neither ELISPOT nor proliferation assays were statistically different at LTI compared to ITI. While clearly above pre-vaccine responses, the drop in DTH was statistically significant (p < 0.05). Similarly, the increase in Treg cells and circulating TGFβ was also statistically significant. An increase of >200 % in PSA-doubling time at any point during the study was observed in 6/17 patients, with 3 retaining this effect to 5 years.

Conclusions: AE37 generates immunological memory associated with possible clinical efficacy in spite of Tregs and TGF-β levels returning at 4 years after being decreased for up to 6 months after initial AE37 vaccination. These results support further randomized testing of the AE37 vaccine.

The publish only abstract is interesting. We know from an earlier publication (see here) that nine of the subjects who completed the vaccine series were stage IV metastatic (later stage) patients with bone metastases. In that earlier publication, the researchers noted,

The maximum increase of specific IFN-γ–producing T cells in response to vaccination with AE37, detected by ELISPOT and expressed as mean fold increase from baseline levels, was higher in stage II-III and castrate-sensitive patients compared with stage IV and castrate-resistant patients, respectively, although this difference was not statistically significant. Similarly, DTH responses to the vaccine, determined as the difference of post vac minus baseline DTH, were statistically significantly lower in stage IV patients.

In that report, the researchers conclude that,

In conclusion, the use of the AE37 immunotherapeutic vaccine is a novel strategy for managing patients with prostate cancer. This clinical trial shows that the vaccine is safe and immunologically active. However, proof of clinical benefit will require a phase II trial in a homogeneous group of patients with less extensive disease, including disease-free patients at high risk of recurrence.

Therefore, it appears reasonable to assume that results for the Phase I study would be even more positive if the appropriate traget population had been identified, with booster innoculations to prolong the effectiveness of the vaccine. The incease of >200 % in PSA-doubling time at any point during the study for 6/17 patients is remarkable, and since this earlier Phaser I study was initiated Antigen Express has learned much about the vaccine. Booster series have been added to the breast cancer Phase II, with a targeting of lower HER2 expressing early stage subjects.

As we can see with the first ASCO abtract, titled "Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study", Antigen Express is on the right tract in developing AE37. The prostate cancer Phase I illustrates that AE37 stimulates long lasting memory, and the new booster program can help add to the desired effect. The second ASCO abstract,titled "Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence", highlights the strong safety profile of AE37/GM-CSF + booster, so all appears on track, even if these abstracts don't yet outline final results of the ongoing Phase II study in early stage HER2 breast cancer patients, which may be needed to lift GNBT's dreadful stock. Those final results may come later this year.

Click on the abstract titles to view the content at ASCO's 3013 Annual Meeting website.

Two Abstracts Pertaining to the AE37 HER2/neu Vaccine Accepted as Poster Presentations at ASCO 2013

Two abstracts pertaining to Antigen Express' AE37 Her2/neu vaccine have been accepted for poster presentations at the 2013 American Society of Clinical Oncology ("ASCO") Annual Meeting. The annual ASCO meeting is being held in Chicago, Illinois from May 31 through June 4, 2013.

The abstract titles, with the name of the lead author, were revealed today with the launch of the meeting's iplanner. Here is the available information:

Abstract #3095

Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study.

Eleftheria A. Anastasopoulou

Abstract #3097

Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence.

Alfred F. Trappey, MD

The iplanner is available for review here.

A Transcript of Dr. James Anderson's Comments During Today's Generex Conference Call

CEO Mark Fletcher:

Last week, we announced that our partner in India, Shreya Life Sciences, has completed it’s phase three trial of General Oral-lyn in patients with type II diabetes and submitted the results to the Indian government with a view to securing approval for the marketing of the product. I will now ask Dr. Anderson to comment on this positive development and it’s impact on our own plans for Generex Oral-lyn in the clinical and regulatory sphere. Dr. Anderson?

Dr. James Anderson:

Thank you, Mr. Fletcher. Good morning, I will address three topics today with regard to Generex Oral-lyn buccal insulin spray product program. First, a review of trial O84, part of which was discussed at a prior AGM, second, the completion and regulatory submission of the Oral-lyn phase three study in India and the partnership of Generex and Shreya Pharmaceutical to produce, distribute, market Oral-lyn in India, thirdly, the planned improvements in the Oral-lyn formulation for global registration will be discussed.

Previously, I’ve provided data on patients who had completed the O84 clinical trial, a six month trial with a six month extension comparing Oral-lyn to injected regular insulin in patients with type I diabetes. You will recall that in that patient segment of completers, as measured by hemoglobin A1C, the metabolic control achieved with Oral-lyn was equivalent to the control of patients randomized to injected regular insulin. For a number of significant reasons, the data from the O84 trial was re-examined, re-analyzed and the final report re-written.

While the positive data from the small group of completers did not change appreciably, the trial as a whole did not meet the primary objective of showing non-inferiority of Oral-lyn to injected regular insulin. Although the study did yield some useful information, why did the study fail to meet the primary objective? The major reason was that two-thirds of the subjects randomized to receive Oral-lyn failed to complete the study. The majority of those patients who dropped out did so during the first one to three weeks of therapy. While a few study sites were in the U.S. and Canada, the majority were in Eastern Europe, in the new republics of the former Soviet Union.

More than two-thirds of the patients enrolled in the study were given educational instructional materials not in their native languages. As importantly, two-thirds of the physicians and healthcare professionals did not have complete material in their native language. We believe that this was the flaw that resulted in a lack of understanding of how to use Oral-lyn correctly which produced an excessive dropout rate that led to not achieving the primary objective.

For this study, the pre-specified non-inferiority margin was 0.50 percent. The 90 percent confidence interval, which is that range of values to finding a difference between two parameters, was calculated to be 0.24 percent to 0.53 percent. Since the 0.50 non-inferiority margin is in between the upper and lower values of the confidence interval, the study was not able to show that Generex Oral-lyn was non-inferior, that is equal to, the injected human insulin. The extremely low number of patients completing that trial directly affected the values of the confidence interval, but even with that huge dropout, the upper limit of the 90 percent confidence interval was very close to the pre-specified non-inferiority margin of 0.50 percent. The study almost was successful.

In sharp contrast, the phase three trial conducted in India, a Shreya Life Sciences, was an excellent example of the way a trial should be conducted. This study, 12 week parallel controlled study comparing Oral-lyn to injected rapid insulin in patients with type II diabetes, was conducted at 14 sites in India with 209 patients put on drug. The educational materials and the informed consents were translated into nine different languages so that each individual participant and his or her representatives could read the information in a language in which they were conversant and comfortable. In this study, only 11 of the 209 subjects, five percent, dropped out of the trial.

While a manuscript of the full trial results has been submitted to an international journal of clinical diabetes and thus the detailed results are embargoed until publication, I can share that there was a statistically significant improvement in the hemoglobin A1C of those patients randomized to Oral-lyn compared to injected insulin and that the statistically significant improvement in metabolic control occurred much more rapidly in the Oral-lyn treated group than in the injected insulin group. Shreya Life Sciences and their investigator are excited about the results and so are we.

The results of that trial were also submitted to the drug controller general of India, the Indian regulatory authority, in December of 2012 as part of the dossier to gain final approval for marketing in India. We are extremely pleased to announce that Shreya anticipates approval for the sale of Oral Recosulin, which is their trademark for Oral-lyn in India, within mid 2013.

In the country of India, the International Diabetes Federation has estimated there are over 50 million people with diabetes mellitus. Generex is currently working with Shreya to transfer the technology to facilitate the local manufacturing of Oral-lyn to global standards to ensure continuous product availability. We are also working with Shreya in the planning and design of patient and professional educational materials, product launch materials and sales and marketing strategies.

Now I’d like to address the planned improvements in Generex Oral-lyn. A review was conducted last year with insulin formulation chemists, clinical diabetologists and diabetes sales and marketing leaders. The new techniques in protein chemistry and pharmaceutical formulation science suggested that with minimal changes in the production process and contents of the components, we could improve Oral-lyn less increasing the convenience, compliance and safety for patients by producing a more concentrated Oral-lyn formulation that would allow dosing in the average patient to be reduced to fewer sprays.

We have developed a clear and complete plan for identifying the modifications to the Oral-lyn formulation and rapid mist delivery device to ensure two to three international units of bio available insulin per spray. Our new program encompasses a pharmaco kinetic and gluco dynamic trial design and clinical study plan for conducting trials with appropriately validated methodology. These short studies will demonstrate the integrity and bio viability of the insulin formulation delivered by the device, assess the pharmaco kinetics using validated methodology and appropriately designed clinical models, confirm the bio availability of the delivery insulin and assess the gluco dynamic response in fasted, post meal and (inaudible) clinical models.

Our planned final phase three trial required by the USFDA for registration will examine the reproducibility and intrasubject variability both short term and over the duration of the study. We will also assess intrinsic and extrinsic factors that could affect absorption such as pharyngeal infections, smoking and vascular medications. These studies will also provide data demonstrating the ability of Oral-lyn to achieve metabolic results that are not possible with subcutaneous injected insulins, even with the rapid acting insulin analogs available today. This will allow our marketing partners to justify any potential price premium over injected insulin and help ensure a more rapid uptake of view in the medical community.

The obvious question that many of you may be asking right now is, “Why are you changing the formulation if the current formulation is good enough to sell in India?” I’m not going to immediately defer to the bandwagon of blaming all of our ill on Coca-Cola, McDonald’s and the Ford Motor Company, but an unpleasant reality of western civilization is that we are more obese than our Asian brethren. With our increased weight, our mealtime insulin doses are also higher, frequently in the range of double or more. So while the less obese and better exercised patients in India can easily use the current formulation of Oral-lyn, a stronger formulation is required for the average patient in North America. Since we anticipate that obesity will continue to become a more prevalent worldwide, we are already in discussions with our partner, Shreya, for future production and sales of the improved Oral-lyn formulation in India and other global markets as well.

In summary, we’re quite excited and pleased with the progress we have made with Generex Oral-lyn over the last six months. Conduct of correctly designed and well-implemented clinical studies continue to demonstrate the validity and efficacy of the Oral-lyn product and the platform. The anticipated approval, launch and sales of Oral-lyn in one of the largest populations of diabetes mellitus in the world signifies the new milestone in the successful reorganization of Generex Biotechnology. While the Oral-lyn reformulation, clinical study work and final FDA submission are dependent upon adequate and appropriately timed funding and partnering to meet timeline goals, we are confident that we are now moving forward in the right direction both for Generex and for its investors.

Thank you and I look forward to our next opportunity to inform you of the additional new programs in diabetes detection, diagnosis, therapy and prevention that are in development in the Generex pipeline.

Emerging Vaccines Take Aim at Preventing Recurrent Breast Cancer

The following article was written by Joe Munch, and published in MD Anderson's OncoLog.

OncoLog, January 2013, Vol. 58, No. 1

Myriad advances have been made in the treatment of breast cancer, and cures are achieved in many patients. However, there are still patients whose cancer recurs, and most of these patients will die of their disease. This indicates a need for other therapies that can be used to prevent recurrent disease. One potential option is breast cancer vaccines.

“Breast tumors are made up of so many different types of cells that we have to use many different drugs and therapies to treat them,” said Jennifer Litton, M.D., an assistant professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center. “Vaccines come at the cancer in a totally different way than our current systemic therapies do.” Vaccines thus may augment the effects of adjuvant treatments currently used to forestall recurrence.

Potential clinical role

Several types of adjuvant therapy are used to prevent breast cancer from returning; the therapy or combination of therapies used depends on the individual patients and their disease. For example, radiation therapy is used for patients who have undergone breast-conserving surgery, and chemotherapy may benefit patients at high risk of recurrence. Hormonal therapy with tamoxifen or an aromatase inhibitor is used in patients with estrogen receptor–positive disease, and immunotherapy with trastuzumab is used in those with tumors that highly express human epidermal growth factor receptor 2 (HER2).

Today, several clinical trials are evaluating the use of breast cancer vaccines—not as an alternative to currently available preventive therapies for recurrent disease but as an additional adjuvant therapy.

“This is a novel approach specifically for people who want another form of therapy to decrease the chance of the cancer coming back,” Dr. Litton said. “People are looking for something extra that may improve their outcome but doesn’t expose them to a lot of extra toxicity.”

Peptide vaccines

Cancer vaccines stimulate patients’ immune systems to recognize and kill tumor cells. The vaccines consist of a tumor-associated antigen that, once introduced into a patient’s body, elicits an immune response. Several systems have been devised to deliver tumor-associated antigens into the body, including whole-cell vaccines, viral vector vaccines, and dendritic cell vaccines, which are custom made from the patient’s own white blood cells. The only therapeutic cancer vaccine currently approved by the U.S. Food and Drug Administration is sipuleucel-T (Provenge), a dendritic cell vaccine used in men with metastatic hormone-refractory prostate cancer.

The breast cancer vaccines being investigated at MD Anderson are of a fourth type, peptide vaccines. Peptide vaccines are made by taking a small amino acid sequence (peptide) from a tumor-associated antigen. The tumor-associated antigen most frequently used in breast cancer vaccines is the HER2 oncoprotein, which promotes tumor growth.

Once taken from the antigen, the peptide is mixed with an immunoadjuvant to help stimulate an immune response. The immunoadjuvant used in the trials being conducted at MD Anderson is granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been used primarily to treat neutropenia in transplant recipients.

When the peptide–GM-CSF combination is injected, GM-CSF stimulates the dendritic cells in the area of injection to take up and process the peptide so that it can be better presented to the immune system. The length of the peptide dictates the type of immune cell it stimulates.

Current clinical studies

Several HER2-derived peptide vaccines are being studied in clinical trials at MD Anderson. Although the vaccines are based on a HER2 peptide, they have the most benefit in the 60% of breast cancer patients with low HER2 expression (1+ or 2+ by immunohistochemistry).

Phase III trial of E75

The E75 vaccine (NeuVax) is the most studied of the HER2-derived peptide vaccines. The 9-amino-acid peptide E75 binds with major histocompatibility complex (MHC) class I molecules to stimulate CD8-positive T cells; when these T cells recognize a target as foreign, they attack it and release cytotoxic enzymes to kill it. Because E75 is an MHC class I peptide, the vaccine works only in patients whose cells are positive for human leukocyte antigen (HLA)-A2 or HLA-A3; only cells with those HLA types will present the peptide on the cell surface to activate T cells.

In May 2012, Elizabeth Mittendorf, M.D., Ph.D., an assistant professor in the Department of Surgical Oncology, and her colleagues published the 24-month landmark analysis of their phase I and II trials of E75. The group’s findings opened the door to the phase III PRESENT (Prevention of Recurrence in Early-Stage, Node-Positive Breast Cancer with Low to Intermediate HER2 Expression with NeuVax Treatment) study, currently the only phase III trial of a breast cancer vaccine. Dr. Mittendorf is the overall principal investigator of the multinational study.

This randomized, double-blind, placebo-controlled trial will enroll approximately 700 breast cancer patients who were rendered disease free following standard treatment. Patients must be positive for HLA-A2 or HLA-A3 and have had cancers that were scored as HER2 1+ or 2+ by immunohistochemistry. The vaccine will be given once a month for 6 months and then given as a booster inoculation every 6 months thereafter through 3 years. Because GM-CSF causes inflammation at the injection site, it will be given to patients in each study group, serving as the immunoadjuvant for the vaccine group and as an active placebo for the control group. The primary endpoint of the study is 3-year disease-free survival.

Positive results from this trial, researchers hope, would eventually lead to indications for the E75 vaccine in the routine care of breast cancer patients. “We are all cautiously optimistic—and excited—as we wait for the results. If they do show that E75 has significant benefit, it could be an amazing opportunity for our cancer patients,” Dr. Litton said.

Phase II trial of GP2 and AE37

The GP2 vaccine works in much the same way as the E75 vaccine. Like E75, the GP2 peptide is 9 amino acids long and binds to MHC class I molecules to stimulate CD8-positive T cells; thus, the vaccine works only in patients who are positive for HLA-A2 or HLA-A3. In contrast, the AE37 peptide, which is longer than the E75 and GP2 peptides, binds to MHC class II molecules and stimulates CD4-positive T cells, thereby eliciting a more robust immune response. Although MHC class II peptides can be HLA-restricted, AE37 is a promiscuous peptide, meaning that blood cells of almost any HLA type can present it. In addition, the AE37 peptide is paired with the Ii-Key protein, which enhances the presentation of the peptide to the immune system.

Both the GP2 and AE37 vaccines are being investigated in an ongoing phase II trial to determine whether the individual vaccines can prevent the recurrence of node-positive or high-risk node-negative breast cancer. Patients are sorted into groups depending on their HLA status and then randomly assigned to receive the appropriate vaccine plus GM-CSF or GM-CSF alone (as the control).

The AE37 trial’s planned interim analysis revealed that at a median of 22 months, the recurrence rate in the vaccinated patients was 10.3%, whereas the recurrence rate in the control group receiving only GM-CSF was 18.0%. The difference represents a 43% reduction in recurrence rate.

“These data are encouraging,” Dr. Mittendorf said. “Obviously, we need longer follow-up, and we need to finish accrual in the trial, but the data suggest that it is reasonable to look forward to investigating the AE37 vaccine in a phase III setting.”

The interim results for the GP2 vaccine are not yet available.

Potential benefits

One of the benefits of peptide vaccines such as those being investigated at MD Anderson is that they can be given “off the shelf.” This makes them more convenient and less expensive than the custom-made dendritic cell vaccines.

Dr. Litton, who has referred a number of patients to the breast cancer vaccine trials, said that patients’ enthusiasm about participating in a vaccine trial has been overwhelmingly positive. “Some patients tell me that they feel empowered by using their own bodies, their own immune systems, to fight the cancer,” she said.

But the main reason the trials are so popular with patients is that the vaccines offer a potential anticancer benefit with very little risk of toxicity. Most patients have a grade 1 or 2 local toxic response, which means redness at the injection site; and some patients experience grade 1 or 2 systemic symptoms, mostly in the form of minor flu-like symptoms for 4–6 hours after receiving the vaccine.

“These are people who have gone through chemotherapy, lost their hair, and had terrible gastrointestinal side effects, toxicity in their nails, and all those other things,” Dr. Mittendorf said. “So a treatment that is basically not toxic is very attractive.”

Dr. Litton echoed Dr. Mittendorf’s sentiments. “It has not been a hard trial for people to become interested in. In fact, I’ve had several people come from different parts of the country just to be part of the trial,” Dr. Litton said. “And we really appreciate all the patients who have stepped forward to participate. It’s always important to encourage people to participate in clinical trials; otherwise we could never move forward with therapies such as this.”

These vaccines are not for everyone, however. Earlier clinical trials revealed that the peptide vaccines had limited efficacy in patients with late-stage, metastatic breast cancer.

“There’s a long list of reasons why these vaccines are not set up to be administered to patients who have diffusely metastatic disease,” Dr. Mittendorf said. “It would be difficult, with a peptide vaccine, to mount enough of an immune response to eradicate bulky disease. The microenvironment and immune environment around tumors change as tumors progress, so bulky metastatic tumors also have a less favorable environment for the immune system to function in. And a lot of patients with diffusely metastatic disease have received multiple lines of chemotherapy, which we suspect has a detrimental effect on the immune system.”

Future directions

The future of breast cancer vaccines holds many possibilities. Antigens such as cyclin E and folate-binding protein may be targeted for vaccination. Novel immunoadjuvants are being developed that may elicit an immune response more potent than that elicited by GM-CSF. And new approaches using vaccines and harnessing other aspects of the body’s immune system against recurrent breast cancer may be forthcoming.

“I would like to see some of these vaccines combined with other exciting immunotherapies that are coming on board,” Dr. Mittendorf said. For instance, a vaccine could be paired with a drug that inhibits CTLA-4, a protein that downregulates T cells. “Ipilimumab, an antibody that targets CTLA-4, could be used to take the brakes off the immune system. A vaccine would stimulate the T cells, and the anti–CTLA-4 treatment would allow them to proliferate,” she said.

Eventually, such vaccines could be used to treat patients much earlier in the course of their disease. “I think it would be an exciting route to look forward to in the frontline setting as well,” Dr. Litton said. “We could potentially cure more people up front at the time of diagnosis.”

Please click HERE to view this article at OncoLog.

Army Surgeons Present New Research on Cancer Vaccine

The following press release was issued by the U.S. Army Medical Department on October 3rd, 2012:

CHICAGO, Oct. 3, 2012 – Yesterday U.S. Army surgeons exhibited new research findings at the American College of Surgeons Clinical Congress.

The poster presentation titled, "Assessment of Disease Features and Immune Response in Breast Cancer Patients with Recurrence after Receiving AE37, a HER2 Peptide Vaccine," outlined outcomes of injecting AE37, a HER-2 derived vaccine, in breast cancer survivors following completion of standard therapy. Those who received injections of AE37 were more likely to survive disease-free than the control group.

Meanwhile, the poster presentation titled, "A NSQIP Evaluation of Practice Patterns and Outcomes Following Surgery for Anorectal Abscess and Fistula in Patients with and without Crohn's Disease," showed patients with Crohn's Disease (CD) – a form of inflammatory bowel disease – had more aggressive anorectal abscess and fistula disease and suffered more complications following emergency surgery than patients who did not have CD.

AE37 breast cancer vaccine creates robust immunologic response in cancer survivors

The poster "Assessment of Disease Features and Immune Response in Breast Cancer Patients with Recurrence after Receiving AE37, a HER2 Peptide Vaccine," showed after completing standard treatment, breast cancer survivors who received injections of AE37 with granulocyte-macrophage colony-stimulating factor (GM-CSF) – an immune stimulant – were more likely to survive five years disease-free than a control group that received GM-CSF alone. AE37 works by stimulating the immune system to recognize and target for destruction a protein called HER2 that is expressed at some level by most breast cancer cells.

While AE37 did not prevent recurrence in all patients, it provoked an immunologic response in patients across the board, including survivors at high risk of recurrence, those with the hard-to-treat "triple negative" form of breast cancer and those with lower levels of HER2 expression. "Patients with a lower level of expressed HER2 protein, who wouldn't be eligible for the HER2-binding antibody, trastuzumab (Herceptin), had a survival rate of more than 88 percent, compared to 70 percent in the control group," said U.S. Army Capt. John Berry, MD, a research associate. "The vaccine may have benefited patients with less aggressive cancers."

Study director Col. George E. Peoples, M.D., explained how the Cancer Vaccine Development Program differs from other groups investigating cancer vaccines. "Our program was one of the first to enroll cancer survivors with healthy immune systems rather than focus on people with end-stage, metastatic cancer. Our goal is to increase health and survivorship in this group, including specifically those with a high risk of cancer recurrence."

This study is part of an ongoing prospective, multi-center, randomized, single-blinded phase IIb adjuvant therapy trial. AE37 was co-developed by the Cancer Vaccine Development Program, housed at Brooke Army Medical Center in San Antonio, Texas.

Capt. Diane F. Hale, M.D., Sonia Perez, Ph.D., Capt. Timothy Vreeland, M.D., Capt. Dabney Raetasha, M.D., Michael Papamichail, M.D., Ph.D., Maj. Guy T. Clifton, M.D., Capt. Alan Sears, M.D., Sathibalan Ponniah Ph.D., and Elizabeth A. Mittendorf, M.D., FACS, also participated in the study.

Generex's AE37 Vaccine Press Release Appears Off Target

I'm someone so clumsy that I'd be better off throwing an apple at an arrow, as opposed to an attempt at shooting an arrow at an apple. There's a better chance that I'd shoot the arrow at my foot, or straight up in the air, so I'd only split my head. The wiser move is to simply eat the apple, and forget the arrow. Generex, and their wholly owned subsidiary Antigen Express, appear equally clumsy when it comes to writing press releases detailing the latest data that researchers are presenting for their novel AE37 HER2/neu peptide vaccine. I'm joking a bit, so I hope the good folks at Generex have a sense of humor. Yet, their follies in this area are true.

The latest example of the reporting of interim efficacy results for AE37 in a company press release that are actually lower than the lead researcher's findings came a few hours ago. Here's a quick look. The following sentence is from Generex's press release dated today, where they provide details of a study abstract that will be presented at the ASCO Breast Cancer Symposium this Friday:

While the study showed an overall reduction of 42% in the risk of relapse in all patients of the study who received the vaccine, the reduction in the risk of relapse was 66% in patients with low expression of the HER2 oncoprotein who were classified as having triple negative breast cancer.

That's impressive data, although the actual results are even better. The lead author of the study is Dr Elizabeth Mittendorf from MD Anderson. The following two sentences are from the study abstract:

"After a median follow-up of 22.3 months, the disease-free survival (DFS) rate in the VG is 90.3% vs 81.1% in the CG (p=.46), a 49% risk reduction."

"The DFS rate in the VG of TNBC patients is 83.3% vs 47.6% in the CG (p=.23), a 68% risk reduction."

Generex reports that there was a 42% risk reduction for relapse in all patients who received the vaccine (VG) in the latest interim look at the ongoing study, but the true risk reduction as stated in the abstract is 49%. Generex also reports that there was a 66% risk reduction for relapse in subjects classified as having triple negative breast cancer (TNBC), but the true risk reduction as stated in the abstract is 68%. Here's a link to the press release, and a link to the abstract.

In June, during the ASCO Annual Meeting, Generex's AE37 vaccine was the topic of discussion in a podium presentation titled "From bench to bedside: The use of the li-Key technology to improve helper peptides for clinical use in cancer vaccines". The report highlights earlier interim results for the same ongoing study as discussed today. At the time, Generex issued a press release informing of the presentation, and the following sentence described key data:

With a median follow-up of 22 months in breast cancer patients, Kaplan Meier projections estimate recurrence rates of 10% in vaccinated patients versus 17% in the control group, a risk reduction of 41%.

Once again, that's impressive data. However, Generex also misreported the true findings. The lead author of this report is Dr Tim Vreeland from the San Antonio Military Medical Center. The following sentence reveals the actual data from his presentation:

With a median f/u of 22 months, Kaplan Meier projections estimate recurrence rates of 10.3% in the VG compared to 18% in the CG; a 43% risk reduction

Generex reported that there was a 41% risk reduction for relapse in all patients who received the vaccine up to that time period, with recurrence rates of 10% in the AE37 group vs. 17% in the control group. Dr Vreeland actually reported a 43% risk reduction, with a relapse rate of 10.3% in the AE37 group vs. 18% in the control group. Here's a link to Generex's press release from June, and a link to the actual abstract.

If we go back a little further in time, say to 2009, we may recall this press release from Generex that came one day after an errant corporate update for this same Phase II study. This press release came on the heels of the first look at early efficacy findings, as were presented at the San Antonio Breast Cancer Symposium in December 2009:

Generex Clarifies Previous Announcement of Breast Cancer Study Interim Results

WORCESTER, Mass., Dec 15, 2009 (GlobeNewswire via COMTEX News Network) -- On December 14, 2009, Generex Biotechnology Corporation (Nasdaq:GNBT) (www.generex.com) issued a press release announcing the presentation of interim results from a Phase II efficacy study of a novel immunotherapeutic vaccine being developed by its wholly-owned subsidiary, Antigen Express, Inc. (www.antigenexpress.com), at the 32nd Annual San Antonio Breast Cancer Symposium (www.sabcs.org).

That press release stated that "only half the number of patients in the treatment arm of the study relapsed compared to those not receiving the vaccine," and that "the results presented at the conference were those observed in patients 13.5 months after treatment." Those statements were incorrect. In fact, as COL George Peoples, MD reported to the symposium, at a median follow-up of 13 months, there were NO relapses in patients receiving the AE37 immunotherapeutic vaccine for breast cancer (0 of 49 patients) while relapses were observed in the control group (5 of 71 patients).

The ultimate goal of the study is to demonstrate that, after a follow-up period of 24 months, the relapse rate in the AE37 group of the study is less than half the relapse rate in the control group. The interim results of this study reported by COL Peoples clearly show that the study is on track to achieve that positive endpoint.

Putting 2009 aside, if we just went with the recent information provided by Generex's press releases, we would assess that the study is going well, with a risk reduction of relapse for all subjects staying relatively even, improving from 41% to 42%, as additional subjects are enrolled into the study. From the abstracts, we can see that the risk reduction was factored at a higher 43% in June, and has since improved to 49%.

What's the difference between a 42% risk reduction in relapse vs. 49%? The difference is an extra few early stage breast cancer patients who are participants in this remarkable study that will continue to lead healthy lives, all because Generex and Antigen Express have done an extraordinary job in creating a revolutionary cancer vaccine, even if they struggle with media relations. Generex and Antigen Express may trip on a pebble, such as writing a press release, yet they appear ready to move what was thought to be the toughest of all mountains, CURING CANCER!

Reasearchers from MD Anderson Present Interim Phase II Date for AE37 at ASCO's 2012 Breast Cancer Symposium

Early Efficacy Analysis of the AE37 Vaccine in Patients with HER2 Low-Expressing and Triple-Negative Breast Cancer.

Abstract No:
109

Author(s):
Elizabeth Ann Mittendorf, Sonia A. Perez, Diane F. Hale, Timothy J. Vreeland, Alan K. Sears, Guy T. Clifton, Alexandros Ardavanis, Nathan M. Shumway, James L. Murray, Sathibalan Ponniah, Michael Papamichail, George Earl Peoples

Abstract:

Background: Peptide vaccines comprised of HLA class II epitopes, which elicit CD4+ T cell responses, play a critical role in potentiating immune responses. We are conducting a randomized phase II trial of AE37, a hybrid peptide created by the addition of the Ii-Key moiety (LRMK) to the HER2 helper epitope, AE36 (HER2 aa776-790). Here, we present efficacy data focusing on outcomes in patients with low HER2 (IHC 1+ or 2+) expression and triple negative breast cancer (TNBC).

Methods: The trial is enrolling node positive or high risk node negative breast cancer patients with any degree of HER2 expression (IHC 1+, 2+ or 3+ or FISH > 1.2) rendered disease-free following standard of care therapy. Patients are randomized to receive either AE37+GM-CSF or GM-CSF alone in 6 monthly intradermal inoculations followed by booster inoculations administered every 6 months.

Results: The trial has enrolled 254 patients; 105 in the vaccine group (VG) and 149 in the control group (CG). After a median follow-up of 22.3 months, the disease-free survival (DFS) rate in the VG is 90.3% vs 81.1% in the CG (p=.46), a 49% risk reduction. Evaluating patients with low HER2 expression (IHC 1+ or 2+), there are 53 VG patients and 77 CG patients. The groups are well-matched with respect to the percentage of patients with high grade tumors, tumors > 2cm, the rate of node positivity and ER/PR status (all p>.5).

The DFS rate in the VG of low HER2 expressers is 89.8% vs 68.2% in the CG (p=.12), a 68% risk reduction.

When limiting analyses to patients with TNBC (ER/PR negative, HER2 1+ or 2+), there are 13 VG patients and 23 CG patients. The groups are again well-matched with the exception of control patients having a larger percentage of tumors > 2 cm (70% vs 31%; p=.02).

The DFS rate in the VG of TNBC patients is 83.3% vs 47.6% in the CG (p=.23), a 68% risk reduction.

Conclusions: Early analyses suggest clinical benefit to vaccination with AE37, particularly in patients with low HER2-expressing tumors. Importantly, the benefit appears to persist in TNBC patients. Patients will continue to be followed per protocol for 5 years; however, these data suggest that a subsequent phase III trial should evaluate the vaccine in patients with low HER2-expressing disease to include TNBC.

Here is a link to the abstract.

Let's get wonky! Generex Pipeline Review's unexpert discussion:

The most differential aspect between the results Dr Mittendorf et all present at this week's ASCO Breast Cancer Symposium vs. the ASCO Annual Meeting from June is the inclusion of disease free survival rates for triple negative cancer subjects. Triple negative patients test negative for estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-). According to breastcancer.org,

These negative results mean that the growth of the cancer is not supported by the hormones estrogen and progesterone, nor by the presence of too many HER2 receptors. Therefore, triple-negative breast cancer does not respond to hormonal therapy (such as tamoxifen or aromatase inhibitors) or therapies that target HER2 receptors, such as Herceptin (chemical name: trastuzumab). However, other medicines can be used to treat triple-negative breast cancer.

About 10-20% of breast cancers — more than one out of every 10 — are found to be triple-negative. For doctors and researchers, there is intense interest in finding new medications that can treat this kind of breast cancer. Early studies are trying to find out whether certain medications can interfere with the processes that cause triple-negative breast cancer to grow.

In the new AE37 study, a much higher percentage (70%) of triple negative subjects within the control group have a tumor size greater that 2 cm, while 69% of triple negative subjects in the vaccine group have a tumor size less than 2 cm. Share cancersupport.org informs that-

triple negative breast cancer tumors are also classified into four stages on the basis of size and lymph-node involvement. Stage I means that the tumor is less than 2 cm in size and there is no lymph node involvement. Stages II and III indicate larger size and degrees of lymph node involvement. Stage IV means that metastasis has already occurred.

With this in mind, it appears that the majority of triple negative subjects in the control group have Stage II tumors, while the majority of triple negative subjects in the vaccine group have Stage I tumors. The difference is noted by the authors of the abstract as being statistically significant, p=.02. For an optimum comparison, the groupings in a planned Phase III study will need to more evenly matched.

However, all of that aside, the results for triple negative subjects within the AE37 arm of the study are quite promising. These subjects have a disease free survival rate of 83.3% at 23.3 months, and the first 24 months appear to be the most critical.

The Oncologist's 2012 article titled Triple-Negative Breast Cancer: An Unmet Medical Need states that "fundamentally, in the early-stage setting, triple-negative breast cancer is associated with earlier versus later events, as well as a shorter period from the time of recurrence until death." They inform in their conclusion remarks that-

triple-negative breast cancer is clearly a distinct subtype, from the perspective of both ER and HER-2, and there may yet be further distinct subclassifications. This disease presentation clearly represents an important clinical challenge. Triple-negative breast cancer is also a surrogate of basal-like breast cancer. Therefore, trials designed to accrue patients with basal-like breast cancer using ER/PR and HER-2 negativity provide an approximation of the triple-negative population, but, as described in the introduction, there is some discordance, including some HER-2 positives and some ER positives among the basals. At present, there is not a clear, proven effective single agent that targets a driving vulnerability in triple-negative breast cancer. However, there are a number of potential therapies currently under investigation that may eventually improve outcomes in these patients.

WebMD estimates that between 10 - 17% of cancers are triple negative. Previous reports estimated that approximately 80% of breast cancer patients could be treated with AE37 if the vaccine gains approval by the FDA. In this estimate, they appeared to be noting subjects that are low and high expressors of HER2/neu. We now see the researchers adding triple negative subjects to their Phase III plannings, and this certainly is a positive development for Generex and Antigen Express.

Currently, Generex's shareholders are waiting to hear an update on the long planned spin out of Antigen Express. Such an update is long overdue, and until then any plans for a Phase III appear to be in a state of limbo. Hopefully, the continued positive results for AE37 bring Generex much needed momentum in their spinout plans for Antigen Express.

One other quick note- during the ASCO Annual Meeting held in June, the researchers noted that they "have enrolled 201 patients to our phase II trial (Vaccine (VG)=103, Control (CG)=98)." This new abstract notes that they have "enrolled 254 patients; 105 in the vaccine group (VG) and 149 in the control group (CG)." The new abstract shows results at 23.3 months, and the June abstract shows results at 22 months. In this update, only 4 subjects have been added to the AE37 arm, while 51 have been added to the control group. Overall, this is the largest controlled study for a peptide based vaccine to treat breast cancer in the adjuvant setting.

As Generex's stock continues to decline, their AE37 breast cancer vaccine continues to shine. At some point, AE37 should have a long lasting positive effect on shares of GNBT, while the more important goal is to cure early stage breast cancer.

Unusual Oral-lyn / IGT Data to be Presented at EASD 2012

The following abstract pertaing to an Oral-lyn study with subjects suffering fgrom impaired glucose tolerance will be presented at the 48th EASD Annual Meeting on October 3rd, 2012 in Berlin, Germany:

Title: Buccal spray insulin in subjects with impaired glucose tolerance: improvement in HbA1c is lost after 6 months wash out therapy

Presentation Time: Wednesday, Oct 03, 2012, 2:30 PM - 2:45 PM

Authors: A. Palermo1, N. Napoli1, E. Maddaloni1, A. Lauria1, A. Soare1, S. Manfrini1, M. Altomare2, S. Leotta2, P. Pozzilli1;
1University campus Bio medico, Roma, Italy, 2Hospital "S.Pertini", Roma, Italy.

Abstract: Background and aims: subjects who develop type 2 diabetes (TD2) pass through a phase of impaired glucose tolerance (IGT). Defects in the action or secretion of insulin are the two major abnormalities leading to development of glucose intolerance. Resistance to insulin progressively increases when passing from normal glucose tolerance through IGT to diabetes, whereas secretion of insulin gradually decreases. Glucose tolerance is assumed to remain normal as long as the beta cell secretion can compensate for insulin resistance. IGT will develop only when insulin secretion fails to compensate fully for such resistance, resulting in postprandial hyperglycaemia that is linked to an increased risk for cardiovascular disease even though there is no progression to diabetes. Many intervention trials have been conducted in IGT patients but only one aimed to decrease post prandial hyperglycaemia. Our previous proof of concept study in subjects with IGT undergoing a prolonged OGTT demonstrated that treatment with 12 puffs of buccal spray insulin was followed by a significant 29.6% decrease in mean plasma glucose at two-hours and a 26.8% decrease at three-hours. Based on these findings a short trial with buccul spray insulin was planed.

Materials and methods: We have designed a randomized controlled trial in patients with IGT comparing a 6 months duration therapy using buccal spray insulin (12 puffs per meal) plus physical exercise and diet (treatment group A, n=16, HbA1c at entry 6.2% + 0.4) vs physical exercise and diet only (control group B, n=16, HbA1c at entry 6.0% + 0.3). Primary endpoint of this study is the reduction of HbA1c of 0.3 % at 6 month treatment between experimental versus control group. Secondary endpoints include the evaluation of antibodies against insulin (IA), changes in body weight, number of hypoglycaemic events during the treatment period and the evaluation of metabolic control at 6 months after the end of the treatment. HbA1c levels, metabolic parameters and insulin antibodies were measured at baseline, at 3 months up to 6 months followed by 6 months wash out.

Results: Subjects treated with buccal spray insulin achieved a significant reduction of HbA1c compared to the control group ([[unable to display character: ∆]] HbA1c 0’- 6 months -0.3% vs +0.09% p= 0.002). At 6 months after the end of treatment, in group A HbA1c levels raised from 5.8 % + 0.3 to 6.1 + 0.5 resulting in loss of previous achieved improvement of metabolic control and 19% of the treated patients developed TD2 ( vs 6% in the control group). There was no significant difference in body weight and no hypoglycaemic or other adverse events were observed during the study period in both groups. No generation of IA was observed in subjects with IGT treated with buccal spray insulin.

Conclusion: These results indicate that buccal spray insulin is an effective treatment compared to diet + physical exercise in patients with IGT in reducing HbA1c without adverse effects. However the beneficial effects of buccul spray insulin is lost within few months of suspension of treatment. A larger trial is required to demonstrate the long term effects of this buccul spray insulin in preventing TD2 in subjects with IGT.

Supported: Educational grant from Generex Biotechnology

This is the oddest study abstract that I have ever read. If the investigator substitutes Oral-lyn with any other prandial insulin, or another glucose lowering drug, the study will illustrate that beneficial effects of the insulin or drug is lost within a few hours after discontinuation of treatment, never mind six months later.

ABC News Features a Report on the AE37 HER2 Cancer Vaccine

Click the word VIDEO to see the ABC news segment.

Antigen Express' Synthetic Peptide Vaccine Technology to be Featured at ASCO 2012

New data from Antigen Express' ongoing Phase II study of the AE37 vaccine will be presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago from 1 - 5 June 2012. Also, an oral abstract presentation followed by a discussion will be given focusing on Antigen Express' proprietory Ii-Key hybrid technology, which has been proven to greatly enhance the potency of CD4+ T helper cells.

AE37, an immunotherapeutic synthetic peptide vaccine to prevent relapse in patients who have had breast cancer, was most recently highlighted during a press conference organized by the American Association for Cancer Research, after a presentation titled "Immune Response Assessment in a Phase II Trial of AE37 HER2 Peptide Vaccine" by Dr. Diane F Hale. A press release from the AACR regarding that presentation can be found here.

On April 25th, ASCO unveiled the eplanner for their Annual Meeting, which opened the door to finding the titles of the new presentations. Full abstracts for the Annual Meeting will be available on ASCO's website after 6 pm on May 16th. Here is what we have learned so far:

Abstract #625

An assessment of disease features and immune response in breast cancer patients that did not recur after receiving HER2 peptide, AE37 vaccine in a randomized phase II trial.

Diane F. Hale, MD, Poster Board: #12D

This poster will be presented during the "Breast Cancer - HER2/ER Sessions on June 2nd between 8:00 am and 12:00 pm in S Hall A2.

Abstract 2508

From bench to bedside: The use of the li-Key technology to improve helper peptides for clinical use in cancer vaccines

This is an oral abstract presentation being given by Timothy J Vreeland, with a discussion to folllow moderated by John Timmerman, MD. This highlighted event will be heard Monday, June 4th, during the "Developmental Therapeutics - Clinical Pharmacology and Immunotherapy" session held between 3:00 and 6:00 pm in the E Arie Crown Theater.

Be on the lookout for Generex, the parent company of Antigen Express, to provide more detailed updates as ASCO approaches.

Two Late Breaking Abstracts Featuring Antigen Express' AE37 Peptide Vaccine for HER2/Neu Breast Cancer Patients to be Presented at AACR 2012

The AACR Annual Meeting will highlight the best and latest findings in all major areas of cancer research. Cancer researchers continue to make incredible strides and breakthroughs, with an impact on global health. The theme of the AACR Annual Meeting 2012, “Accelerating Science: Concept to Clinic,” reflects this amazing progress and emphasizes the synergy between basic, clinical and translational research that will continue to lead to effective cancer therapies and prevention strategies. The meeting takes place March 31-April 4 in Chicago.

Two late breaking abstracts featuring Antigen Express' AE37 Peptide Vaccine for HER2/Neu breast cancer patients will be presented at the AACR Annual Meeting. The titles of the abstracts, and names of the authors, have been made available at the meetings website:

Late-Breaking Poster Session
LBPO.IM01. Late-Breaking Research: Immunology
Mon, Apr 2, 1:00 - 5:00 PM
Abstract Number:
LB-130

Presentation Title:
Immune reconstitution after chemotherapy correlates with increased in vitro immune response in breast cancer patients undergoing peptide vaccine therapy

Location:
McCormick Place West (Hall F), Poster Section 40

Author Block:
Timothy J. Vreeland, Raetasha S. Dabney, Diane F. Hale, Alan K. Sears, Guy T. Clifton, Athina Zacharia, Yusuf Jama, Anna Chiplis, Mohamed Mursal, Nathan M. Shumway, Ritesh Patil, Jarrod P. Holmes, Elizabeth A. Mittendorf, George E. Peoples, Sathibalan Ponniah. San Antonio Military Medical Center, San Antonio, TX, Cancer Vaccine Development Lab, USUHS, Bathesda, MD, Roswell Park Cancer Institute, Buffalo, NY, Redwood Regional Medical Group, Santa Rosa, CA, UTMD Anderson, Houston, TX

Late-Breaking Poster Session
LBPO.CL01. Late-Breaking Research: Clinical Trials
Tue, Apr 3, 8:00 AM - 12:00 PM
Abstract Number:
LB-218

Presentation Title:
Immune response assessment in a phase II trial of AE37 HER2 peptide vaccine

Location:
McCormick Place West (Hall F), Poster Section 40

Author Block:
Diane F. Hale, Timothy J. Vreeland, Raetasha S. Dabney, G Travis Clifton, Alan K. Sears, Efi Pappou, Eleftheria Anastasopoulou, Alexandros Ardavanis, Sathibalan Ponniah, Michael Papamichail, Sonia Perez, Nathan Shumway, George E. Peoples, Elizabeth Mittendorf. Brooke Army Medical Center, Ft. Sam Houston, TX, St. Savas Cancer Hospital, Athens, Greece, Athens, Greece, Cancer Vaccine Development Lab, U.S. Military Cancer Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, University of Texas MD Anderson Cancer Center, Houston, TX


The AACR 2012 website can be found by clicking here.

Antigen Express' AE37 HER2 Peptide Vaccine Named to Shortlist for 5th Annual ViE Awards

Antigen Express' lead vaccine, the AE37 HER2/neu synthetic peptide vaccine, has has been named as a nominee for the BEST THERAPEUTIC VACCINE (approved or in development) according to the shortlist published today for the 5th Annual Vaccine Industry Excellence (ViE) Awards. The ViE awards, sponsored by Novartis Vaccines and Diagnostics, were created to recognize the accomplishments and contributions of companies and individuals in the vaccine industry over the previous 12 months.

The full list of nominees in the Best Therapeutic Vaccine category are:

•Advaxis: ADXS-HPV - HPV

•Antigen Express: AE37 - Breast cancer

•BioSante Pharmaceuticals: GVAX

•Galena Biopharma: NeuVax - Breast cancer

•ImmusanT: Nexvax2 - Celiac disease

•Inovio Pharmaceuticals: VGX-3100 - Cervical cancer

The ViE Award nominees are voted on by those in the global vaccine industry and also judged by a panel of representatives from pharma, biotech, academia, government, non-governmental organizations (NGOs), and public health. Winners are announced at the annual ViE Awards dinner and ceremony, taking place this year on April 11 during the World Vaccine Congress in Washington, D.C. Click on AE37 Vaccine to go to the ViE Awards link on the World Vaccine Congress' website.

Bring it home, Antigen Express!

Antigen Express Makes Progress in Targeting Early Stage Breast Cancer Patients Who Don't Benefit From Roche's Herceptin

As we look forward to cancer research developments in 2012, let's first take a quick look back to 2005. In that year, Genentech, which was acquired for $46.8B in 2009 by Roche (RHHBY.PK), presented findings for their now blockbuster cancer fighting drug Herceptin to a packed room at ASCO's Annual Meeting. Herceptin was found to reduce the risk of recurrence 46% in women with early stage over expressing HER2 breast cancer, according to results reported for the first time from the large scale international HERA study.

Results from HERA showed that Herceptin significantly improved disease free survival at two years, from 77.4% in the observation group to 85.8%. Lisa Hutchinson, the Editor of Nature ReviewsClinical Oncology, wrote at the time that the Herceptin report "received rapturous applause and a standing ovation" from physicians and other attendees at the ASCO session.

Herceptin is a humanized monoclonal antibody that binds to a specific epitope of the HER2 protein on the breast cancer cell surface. Herceptin is a HER2+ breast cancer therapy designed to treat aggressive HER positive metastatic and adjuvant breast cancer. Adjuvant therapy is used after primary treatments, such as surgery or radiation for early stage invasive breast cancer. This additional treatment may reduce the risk that cancer will return.

The IHC test gives a score of 0 to 3+ that indicates the amount of HER2 receptor protein in tumors. Women with IHC positive scores tend to respond favorably to Herceptin. Samples with strong HER2 overexpression, IHC 3+, indicate eligibility for Herceptin therapy. This population makes up approximately 25% of HER2/neu breast cancer patients.

In the first six months of 2011, Roche reported worldwide sales of Herceptin at $3.5B. Approximately 70% of Herceptin's global sales come from adjuvant therapy for women with early-stage HER2 breast cancer following surgery. Immunological agents in development that target patients that exhibit lower expression of the HER-2/neu protein can fill an unmet medical need, and potentially earn far greater sales than Herceptin if they move on to win FDA approval.

During December's San Antonio Breast Cancer Symposium, cancer immunotherapy took another significant step in that direction when interim Phase II results were revealed for Antigen Express' AE37 HER2/neu peptide breast cancer vaccine. Antigen Express is a wholly owned subsidiary for Generex (GNBT.OB) Biotechnology. Here are highlights from the SABCS presentation:

+ Disease-free survival in the low HER2 expressing patients, or the larger percentage of breast cancer patients who are not eligible for Herceptin, was 88.6% in the treated group, n=53, versus 71.9% in the control arm, n=78, at a median follow-up of 22 months.

+ The AE37 vaccine elicits statistically significant peptide specific in-vivo and ex-vivo immune responses, which are maintained for 12 months after completion ofthe vaccine series, while there have been no proliferative changes for control patients.

+ Vaccine patients had statistically significant increases in DTH reactions, while controls had no response.

+ 99% of local and systemic toxicities were grade 2 or less. There have been no grade 4-5 local or systemic toxicities.

+ AE37 represents the only HER2-based peptide vaccine currently being studied in a randomized trial, and its use is not restricted to patients with a particular type of HLA peptide.

There are currently over 250 patients enrolled in the well designed Phase 2 study, the largest breast cancer adjuvant vaccine trial conducted to date. As a result of these findings, Antigen Express announced that they are "assessing the data for potential opportunity to move forward with a Phase 3 clinical development program following an End-of-Phase 2 meeting with the FDA for AE37, which Antigen Express believes, if confirmed, could occur in the first half of 2012". The company will seek a special protocol assessment SPA approval from the FDA. The current ongoing, controlled, randomized, and single-blinded Phase 2 clinical study will continue as planned to enroll a total of 300 women. Further Phase II results, providing a catalyst moment for GNBT's stock, are due within 2012.

Antigen Express is seeking a large Pharma partner to help fund the pivotal Phase 3 clinical development program in women with breast cancer that express low to moderate levels of HER2. A randomized, controlled, double blind study in 1000 HER 1+ 2+ node positive and high risk node negative patients across the US, Europe and Asia is projected to start later in 2012, once a large Pharma partner is in place.

The AE37 cancer vaccine has also been studied in a completed Phase 1 trial with prostate cancer patients demonstrating appropriate dosing and immune activation similar to that seen in the breast cancer trials. Antigen Express is gearing up to move AE37 more rapidly into larger Phase II clinical trial in men with newly diagnosed HER2 positive prostate cancer, which are currently being designed with leading oncologists in prostate cancer. HER-2/neu is over expressed in 11% of ovarian cancers, 39% of prostate cancers, 7 – 34% of gastric cancers, 10 – 82% of pancreatic adenocarcinomas, and is expressed at some level in the majority of epithelial-derived cancers. The potential market for a HER2-based peptide vaccine, such as AE37, is much larger than women with early stage breast cancer or men with newly diagnosed HER2 positive prostate cancer.

Beyond these known developments, a November 2011 patent application reveals plans to further research into combination therapy of AE37 with Herceptin by the Henry M. Jackson Foundation for the Advancement of Military Medicine. The patent details a Phase I study protocol that currently includes 102 disease-free breast cancer patients that over express HER2, IHC 3+, further expanding AE37's potential market grasp. In the patent, the researchers of the study, who are independent of Generex and Antigen Express, state in regards to the study's outcomes that "the in vivo DTH data strongly suggest that AE37 in combination with Herceptin should be more effective at reducing breast cancer recurrence and increasing disease-free survival time than Herceptin alone".

Investing in small biotechs comes with great risk, and each investor is responsible to themsleves to conduct their own due diligence. Generex had previously outlined plans to conduct a reverse stock split of GNBT shares sometime in the near future, only in conjunction with a move to a major exchange, to spin out Antigen Express, while retaining controlling interest, and the spin-out will be accomplished by the issuance of one or more dividends of Antigen Express stock to Generex stockholders. The company has not publicly altered these intentions, and shareholders are awaiting an update on these key areas.

What we may be witnessing is a new era in therapeutic cancer vaccines where the earlier setbacks seen in the overall industry make way to success stories, as Herceptin's success has done for the monoclonal antibody market, as I wrote to an industry leader last year. "I do believe that the cancer vaccine market will follow after the monoclonal antibody market. Once there is a clear cut success story, then all the big pharmas will race to secure their own cancer vaccines to bring to market," expressed Col George E Peoples MD, FACS, Director, Cancer Vaccine Development Program, in a response email. I am increasingly hopeful that Antigen Express' AE37 will prove to be the revoltuionary vaccine that leads the way.

Feuerstein Trips Over Generex in TheStreet

"Ignorance more frequently begets confidence than does knowledge" ~ Charles Darwin

On June 24th, TheStreet's (TST) Senior Biotech Columnist Adam Feuerstein featured Generex (GNBT) Biotechnology and their buccal insulin spray, Oral-lyn, in his Biotech Stock Mailbag. Feuerstein put his spin on a press release Generex issued on June 16th, regarding the updated clinical and regulatory program planned for Oral-lyn. In the news release, Generex outlined the clinical path Oral-lyn will take before a submission for commercial approval will be made to the FDA. Generex had already announced this plan, which was made after the company received feedback from the FDA in late May, at their Annual Meeting on June 8th. The Annual Meeting was offered live via a webcast, and remains available on Generex's website .

Feuerstein began his latest blog about Generex by saying: "It's not in my nature to begin the Biotech Stock Mailbag with a congratulatory slap on my own back, so please allow me to indulge this one time as I revel in the latest failure acknowledged by Generex biotechnology. Last week, Generex finally admitted what every rational human being understood a long time ago: The company's experimental insulin spray for diabetes, known as Oral-Lyn, is not ready for regulatory approval. The ongoing phase III study of Oral-lyn, years behind schedule, is being shut down and cannot serve as the basis for a U.S. approval filing, Generex said."

Feuerstein's reporting that the current Phase III study is being "shut down" is completely false. On June 8th, Generex announced at their Annual Meeting that a "protocol approved" enrollment target of 500 patients has been met, and final results may be available by the end of the year. The company informed that the study results will play a key part in a future NDA, and in designing the next clinical steps to achieve that goal. Subsequently, in a press release issued on June 16th, Generex announced that Phase III "clinical trial 084 in patients with type 1 diabetes will be closed to allow a final data analysis to guide future clinical trial plans. Interim results demonstrated that the type 1 patients treated with Generex Oral-lyn™ maintained metabolic control (hemoglobin A1c) over the 12 month duration of the trial."

Feuerstein also stated in his article that "Generex updated the status of Oral-lyn based on information received in May from officials at the U.S. Food and Drug Administration. The agency, discussing Oral-lyn, raised a "variety of questions about preclinical, clinical, toxicology, manufacturing, and regulatory and product labeling issues related to the wide variety of formulations and prior protocol changes that were made historically."

Feuerstein omitted key parts of Generex's update. Generex, in their update, issued five sentences relating to feedback they received from the FDA, while Ffeuerstein chose to clip out only one. Here is the actual update: "Generex received written guidance from the US Food and Drug Administration (FDA) in late May in response to data submitted on Generex Oral-lyn™. There were no safety issues identified in the clinical trials, nor safety questions raised by the FDA. The FDA did not express any concerns about the RapidMist™ delivery device. There were a variety of questions about preclinical, clinical, toxicology, manufacturing, and regulatory and product labeling issues related to the wide variety of formulations and prior protocol changes that were made historically. Generex's new medical/regulatory team has already responded to the FDA, and is in the process of providing the additional information requested for complete clarification. The FDA guidance placed no limitations or restrictions on the types of patients included or trial designs of current or future clinical studies."

In my opinion, Generex's new medical and regulatory team are working fast to put Oral-lyn on a smarter track to win fuller label approval. The FDA guidance placed no limitations or restrictions on the types of patients included or trial designs of current or future clinical studies, which is a big plus for future labeling plans. Perhaps Feuerstein can explain why he avoided these details, which provide a wider and more accurate picture.

In the comment section of Feuerstein's latest blog about Generex, he stated that "Generex holds a shareholder meeting on June 8, at which a reverse stock split is approved. Management doesn't tell shareholders that another three years of clinical work on Oral-lyn will be required."

In reality, Generex's Senior Scientific Advisor, Dr Joseph Anderson, who previously served as Eli Lilly's Senior Medical Director, gave an update on Oral-lyn's regulatory and clinical standing early into the June 8th Annual Meeting. He clearly informed shareholders that the current Phase III study in Type 1 patients will not be sufficient for a NDA. Dr Anderson remarked on plans for a fuller label, beyond Type 1's, that would provide shareholders the maximum value that should be obtained with Oral-lyn.

Dr Anderson also told shareholders that until Generex completes a consensus meeting with the FDA, he would have a hard time giving guidance on when a NDA may be submitted. He estimated between 36 and 72 months. He said he believed the timeline may actually be significantly shorter, dependent upon pending FDA guidance from the consensus meeting. Dr Anderson informed that Type 1 patients represent less than 10% of people with diabetes, and they need to make include patients with Type 2 diabetes in an additional Phase III study.

Generex alerted that this consensus meeting with the FDA, to obtain agreement with the clinical plan and submission data package, is planned this year. The additional planned clinical studies include a key activity/effect study with the final formulation, and a series of small, well-designed phase 3 studies, potentially conducted as one study with multiple arms. Generex anticipates that these studies will be completed during 2013.

In the comment section which accompanies Feuerstein's blog, I noted his error in stating that Generex did not inform shareholders during the company's Annual Meeting that additional clinical work will be required to gain FDA approval for Oral-lyn. He quickly offered a snarly response, calling me a "dead ender", while avoiding my concerns. I was then blocked from being able to make any additional comments.

One day later, Feuerstein offered a new response. He said, "I stand corrected, sort of... Generex disclosed the FDA communication regarding Oral-lyn -- no imminent approval filing of Oral-lyn, more clinical trials required, taking years at an undisclosed cost -- during its June 8 shareholder meeting. The disclosure wasn't made in Generex's proxy statement or any other SEC filing prior to the shareholder meeting. Generex disclosed the new information at the meeting, presumably after many shareholders had already mailed in their proxy forms to vote on a reverse stock split, among other items. Selective disclosure? Certainly ill-timed disclosure, especially for a management team which desperately needed shareholder approval of the reverse stock split. To get the vote it needed, Generex did what it always does, kept shareholders in the dark."

His comments, in which he acknowledges being corrected on a key charge, require further correcting. Generex has been forewarning of the potential for additional clinical requirements for Oral-lyn, the most recent coming in March. On March 30th, Generex held a press conference and conference call from the NASDAQ MarketSite. While on the conference call, Dr Anderson informed shareholders that there may be a need for additional studies, beyond the ongoing one in Type 1 patients. Obviously, Generex needed to begin Type 2 late stage studies, and we have now heard that these studies are anticipated to be complete in 2013. A transcript of the press conference, and the conference call, where Dr Anderson gave his guidance regarding additional clinical studies, has been available at the SEC's EDGAR filing system since April 6th.

Feuerstein's ended his blog by saying, "I told you so". The blog contains the following disclaimer: "Full disclosure: Generex is suing TheStreet and me regarding prior published columns on Oral-lyn. That litigation is currently ongoing."

Feuerstein's "I told you so" moment may be a reference to a lawsuit Generex filed against Feuerstein, formerly a technology and commercial real estate beat writer, and TheStreet in response to two blogs Feuerstein wrote in March 2010. After the first blog, Generex demanded an apology for misleading or false comments, and TheStreet later placed a disclaimer above his first blog, noting certain inaccuracies, and saying that "TheStreet regrets the error". Generex's subsequent lawsuit had nothing to do with any of these latest developments.

On June 24th, after Feuerstein's latest blog was published, Generex's stock fell over 20%. Generex, like other small biotech companies that Feuerstein reports upon, are in precarious positions as they attempt to navigate the toughest of regulatory environments, while searching to raise large amounts of capital to fund their pipeline. In my opinion, readers of TheStreet deserve better, as do Generex's large base of over 37,000 shareholders.

Generex Takes Part at the American Diabetes Association's Scientific Sessions

The American Diabetes Association's Scientific Sessions takes place from June 24 - 28. Generex is an exhibitor at ADA 2011, and an Oral-lyn abstract has been accepted to be presented at this prestigious industry event.



The image is of Generex's exhibition booth at ADA 2011, courtesy of Generex's Todd Falls. Click the image to enlarge. The abstract being presented at ADA 2011 highlights final six month data from a Phase II study with IGT subjects, or prediabetics, which may present a paradigm change in how they are treated. The following is the abstract from the event:

Treatment of Impaired Glucose Tolerance with Buccal Spray Insulin: A 6 Months Randomised Controlled Trial

Abstract No:
2224-PO

Author(s): ANDREA PALERMO, NICOLA NAPOLI, ERNESTO MADDALONI, ANGELO LAURIA, SILVIA MANFRINI, MARIA ALTOMARE, SERGIO LEOTTA, PAOLO POZZILLI
Location(s):
Rome, Italy

Abstract Body: In patients with impaired glucose tolerance (IGT), upon implementation of life style changes and metformin, a third returns to normal glucose tolerance, a third continues with IGT and the rest goes on to develop clinical type 2 diabetes. An increased risk for cardiovascular disease occurs in the latter two groups even though there is no progression to diabetes. A previous proof of concept study demonstrated that treatment with 12 puffs of buccal spray insulin was followed by a significant 29.6% decrease in mean plasma glucose at two-hours and a 26.8% decrease at three-hours.

We have designed a randomized controlled trial in patients with IGT comparing buccal spray insulin (Ora-lyn) (12 puffs per meal) plus physical exercise and diet (treatment group A, n=16, HbA1c at entry 6.06% + 0.5) vs. physical exercise and diet only (control group B, n=16, HbA1c at entry 5.9% + 0.3). HbA1c levels, metabolic parameters and insulin antibodies were measured at baseline and every 3 months up to 6 months. Primary endpoint is the reduction of HbA1c of 0.3% at 6 month treatment between the experimental and the control group. Secondary endpoints include the evaluation of antibodies against insulin (IA), changes in body weight and number of hypoglycaemic events.

Subjects treated with buccal spray insulin achieved a significant reduction of HbA1c compared to the control group (Δ HbA1c 0'- 6 month -0.34%+0,1 vs +0.07%+ 0,1 p =0,03). There was no significant difference in body weight and no hypoglycaemic or other adverse events were observed during the study period in both groups. No generation of IA was observed in subjects with IGT treated with buccal spray insulin.

These preliminary results indicate that buccal spray insulin is an effective treatment compared to diet + physical exercise in patients with IGT in reducing HbA1c without adverse effects. A larger trial is required to demonstrate the long term effects of this therapy. Here is the link.

According to data from the 2011 National Diabetes Fact Sheet, 79 million people in the U.S. have prediabetes (IGT). As obesity rates rise, so does the need to medically treat this group when the current recommendations of diet and exercise fall short. We have learned in recent weeks that the ongoing Phase III study in Type 1 patients has reached a protocol approved amount of subjects, and will be closed to new recruits. Final data may be available by the end of the year.

We now see positive Phase II results in IGT subjects, and plans to intitiate a Phase III study in Type 2 patients, anticipated to be completed by the end of 2013. A much broader label is being pursued for Oral-lyn, beyond Type 1's, whom make up only 10% of the US insulin market. With no adverse events reported in any studies, or cited as a concern in recent FDA guidance, Oral-lyn represents the next big thing that the current market does not understand.

The Journal of Immunology to Publish Study Detailing Generex Biotechnology's Research Collaboration with the Mayo Clinic in July Edition

The July edition of the Journal of Immunology, a peer-reviewed research publication of the American Association of Immunologists, features an article that will detail the research collaboration between Generex's (GNBT) wholly owned subsidiary, Antigen Express, and the Mayo Clinic. The research is a continuation of scientific study between Antigen Express, lead by President Dr. Eric von Hofe, and the Mayo Clinic's Dr. Keith Knutson, a leader in the field of peptide vaccines in breast cancer. The title of the future article is "MHC Class II Epitope Nesting Modulates Dendritic Cell Function and Improves Generation of Antigen-Specific CD4 Helper T Cells". The abstract and article are not yet available for view, but the title is included in the Journal's future table of contents.

Antigen Express has been developing a series of CD4+ T Cell helper epitopes, based upon their proprietary Ii-Key hybrid technology. Ii-Key is a portion of the MHC class II associated invariant chain, which is known as Ii. Antigen Express explains that Ii-Key facilitates the direct loading of epitopes to the MHC class II molecule groove. Utilizing their technology, Antigen Express' Ii-Key/MHC class II epitope hybrids have shown clinical evidence of greatly enhancing the vaccine potency of the tethered epitope. Antigen Express' most advanced vaccine is AE37, a HER-2/neu hybrid peptide which is currently in a multi-center Phase II study.

The Mayo Clinic's Dr. Knutson has long studied adoptive T Cell therapy strategies to create cancer vaccines designed for immunotherapy of HER-2/neu breast cancer. Adoptive T Cell therapy strategies have largely focused generation of CD8+ T Cells, due to observations that most tumours express MHC class I, but not MHC class II. This gets tricky, so here is some info on CD4+ T Cells vs CD8+ T Cells. CD4+ T Cells recognize antigen-derived peptides in the context of self-MHC class II molecules, while CD8+ T Cells recognize antigen derived peptides in the context of self MHC class I molecules.

The problem Dr. Knutson had previously encountered is that CD8+ T-cells have a short lifespan. Earlier, Dr. Knutson reported that a problem with the use of adoptive T Cell therapy included the lack of CD4+ T cell help. In further work, Dr. Knutson has found that patients immunised with with CD4+ HER-2/neu helper epitopes, such as being developed by Antigen Express, are able to develop long lasting HER-2/neu specific CD8+ T Cell immunity. Specifically, Dr. Knutson found that greater than 60% of patients immunised with CD4+ HER-2/neu helper epitopes, each containing an encompassed HLA-A2 epitope, were able to develop HER-2/neu specific CD8+ T-cell immunity. The CD8+ T Cell response was maintained, in some patients, for at least one year following vaccination.

In contrast, 40% patients immunised with a single CD8+ T Cell HER-2/neu HLA-A2 9-merpeptide, RXI Pharmaceuticals' (RXII) NeuVax, or E75, developed HER-2/neu CD8 T Cell immunity that declined to undetectable levels within 5 months of the last vaccination. AE37 is the HER-2/neu CD4+ T Cell helper containing an encompassed HLA-A2 epitope that outshines E75 given alone in his study. If a main problem for Dr. Knuston's adoptive transfer research had been the lack of CD4+ T cell help, Dr. von Hofe and Antigen Express presented the solution.

Since we know the title of the upcoming research article authored by Dr. Knutson and Dr. von Hofe, with other Mayo Clinic researchers, is "MHC Class II Epitope Nesting Modulates Dendritic Cell Function and Improves Generation of Antigen-Specific CD4 Helper T Cells", we have a clue on where they are going with this research. A 2010 patent by Dr. Knutson, titled "METHODS AND MATERIALS FOR GENERATING T CELLS", explains what is invloved in generating antigen-specific CD4+ T cells. The patent outlines methods and materials for using nested MHC class II epitopes to generate CD4+ T cells. The patent states that the nested MHC class II epitopes provided can include an invariant chain, or Ii, and a MHC class II epitope. The patent is describing his work with Antigen Express, and the upcoming article will provide peer review documentation.

Antigen Express is also involved in a separate collaboration with the Mayo Clinic's Dr. Svetomir Markovic, a distinguished translational researcher with expertise in melanoma trials. That agreement focuses on advancing an immunotherapeutic vaccine for melanoma into the clinic. Generex is planning a spin out of Antigen Express, following approval of a reverse stock split of Generex's shares. Top industry scientists, like those found at the prestigious Mayo Clinic, are already excited about the potential found within Antigen Express' pipeline. I am certainly no scientist, so read my opinions and rough analysis with that in mind, but the potential for Antigen Express is obviously high.

Should Generex's planned reverse stock split proposal be approved, followed by a spin out of Antigen Express, adequate funding may finally be within Antigen Express' grasp, which will serve as the fuel to propel all of this successful research deeper into human studies. The winners in that scenario will be Generex's current and Antigen Express' future shareholders, and most importantly the cancer patients in need of better therapy. We are looking at the future when active immunotherapy will be a commercialized reality, designed by Antigen Express.

Generex Taps Former Eli Lilly Senior Medical Director to Strengthen Clinical and Regulatory Efforts for Oral-lyn

"Having worked with the Generex team in the fledgling stage of Generex Oral-lyn development while at Eli Lilly, I believed then that the product had the potential to become a first-in-class therapeutic insulin treatment even though the companies ultimately headed in different directions as is often the case with early stage collaborations." - Dr. James H Anderson Jr on December 9, 2010

Generex Biotechnology (GNBT) announced on Thursday the appointment of Former Eli (LLY) Lilly Senior Medical Director Dr. James H. Anderson, Jr., MD, FFPM, FACE to the company's Scientific Advisory Board. While such news is not often met with much fanfare, there is an unique element to this announcement when considering the history between Generex and Eli Lilly. A look back may help us realize where we are today as we wait for Oral-lyn's future to unfold.

In September 2000, Generex and Eli Lilly entered into a Development and License Agreement for Oral-lyn buccal insulin. In May 2003, the companies mutually agreed to end the deal. During that two and a half year time period, Lilly did not conduct a single clinical trial to assess either the safety or efficacy of Generex's buccal insulin, while they were actively spending their resources developing the AIR inhaled insulin system, as part of a developmental agreement with Alkermes (ALKS) that was signed in 2001. Lilly had held rights to separate buccal and inhalable insulin programs, and like many large pharmas at the time, they were placing their bet that inhalable insulin was the right path to take.

Like clowns jumping into the same car, many pharma companies were competing with one another to develop inhalable forms of insulin. Pfizer, with partner Nektar (NKTR) Therapeutics, led the foray, and in 2006 they were the first inhalable insulin to win FDA approval. The Exubera story is well known, and I won't repeat the entire saga. Pfizer's failure to earn commercial success with Exubera led to their costly decision in late 2007 to abandon the product and return rights to Nektar. Pfizer recorded a $2.8 billion pretax hit on the product, one of the drug industry's costliest failures. Industry giant Novo (NVO) Nordisk followed Pfizer's lead, and in January 2008 they decided to end development of the AERx inhaled insulin system while the product was deep into costly Phase III testing.

Later in 2008, Lilly terminated their agreement with Alkermes to develop inhalable insulin. Their first quarter results for that year reveal the asset impairment and exit costs associated with betting on the wrong non-invasive insulin to be $132.6 million. Today's news reminds me that sometimes large pharma places the wrong bet, and in this case quite a few found themselves racing down the same dead end. Mannkind is the sole surviving biotech developing a promising form of inhalable insulin, they have a PDUFA date for Afrezza inhalable insulin later this month. This comes after they received a Complete Response Letter a few months ago. Their product offers definite advantages over the failed inhalable insulins such as Exubera, and I actually have come to hope they succeed so diabetics later have greater choices for administering their required insulin.

While thinking of all the money the large pharmas lost while following each other into development of inhalable insulin, I recall a quote attributed to Generex representative Todd Falls in 2003 after Lilly terminated their agreement to develop buccal insulin. He remarked at the time that Lilly "didn't want to put the money into us. Lilly felt, I guess, they had some other interests, and didn't want to be the lead on the project." That decision didn't work out very well for Lilly, and Generex is still here with Oral-lyn being studied in a worldwide Phase III trial, and conditionally approved by the FDA in the first Treatment IND awarded to a diabetes drug.

I continue to believe that Oral-lyn, a tasteless liquid aerosol mist formulation that is administered to the buccal mucosa using a proprietary delivery system, has many advantages over inhalable and injectable forms of insulin, although they must be further proven in the Phase III study. These include the small and simple hand held metered dose device, significantly lowered risk of postprandial hypoglycemia, lack of insulin resistance amongst subjects, an actual decrease in Body Mass Index, with no absorption into the lungs. One spray equals one unit of meal time insulin, and this provides greater flexibility in usage, as well as the ability to take small dose sprays before a snack when a treat simply can not be resisted. The unique time action profile for Oral-lyn may be its greatest advantage, with its ability to mimic the first-phase insulin response seen in a healthy person.

Dr James H Anderson was involved with Oral-lyn when Eli Lilly held developmental rights, and has returned all these years later to talk so optimistically about its development. His statement that he believed even then that Oral-lyn had the potential to become a first-in-class therapeutic insulin treatment even though the companies ultimately headed in different directions helps erase doubt formed by the demise of the deal between the two companies. Since we know that Lilly did not conduct a single test to evaluate Oral-lyn, we can see that a business decision was made void of negative data and full of faulty strategy. Dr Anderson is surely needed to assist Generex, and his background is proven. After all, he was a key player in getting Lilly's blockbuster Lispro approved. That is the type of experience the team at Generex needs to help get Oral-lyn to the finish line.

As Generex continues to align the company with expert talent to strengthen the company's clinical/regulatory efforts, the news always strikes me as sort of a validation of the state of the pipeline. New additions to the Scientific Advisory Board, such as Amgen (AMGN) co-founder Dr Joseph Rubinfeld, Pfizer's (PFE) Vice President of Strategic Alliances and Partnerships Dr Craig Eagle, and now Former Eli Lilly Senior Medical Director Dr. James H. Anderson Jr, also have their own reputations on the line, yet they are quoted making remarks that speak volumes about the hidden worth of Oral-lyn, as well as the company's immunotherapeutic cancer vaccines. Generex's faithful shareholders sure hope some of that hidden worth soon comes into vision.