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.

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.

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.

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.

Talking Big Pharma, Vaccines and Baseball with Generex's Dr. Eric von Hofe

Last week, Generex (GNBT) Biotechnology held a live web cast from Nasdaq's Market Place in NYC, and the event served as an optimistic reminder of the potential of their pipeline, and highlighted the strong group of scientists united in seeing their top drugs and vaccines find eventual commercialization. One day before the Nasdaq web cast took place, I had the opportunity to meet with the top scientist leading their vaccine efforts.

Dr. Eric von Hofe is the President of Worcester-based Antigen Express, a wholly owned subsidiary of Generex. Antigen Express is building an impressive pipeline of next generation synthetic peptide based therapeutics aimed at a variety of major diseases, including cancer and infectious diseases. Dr. von Hofe and I settled in a small NYC deli, and we talked about corporate developments, his background, large pharma, the future he envisions for their platform technology, and my disdain for the Red Sox. Antigen Express is currently evaluating its leading candidate, the novel Ii-key hybrid HER2/neu peptide AE37 vaccine, in a multi-center Phase II trial for patients with breast cancer.

I have followed Dr. von Hofe's career for the last five years, and had briefly met him on two prior occasions. This was the first time I was able to speak with him for an extended time frame, or in an informal setting. I began by asking Dr. von Hofe his thoughts about the vast amount of corporate related changes that have taken place since we last met during Generex's Annual Meeting of Shareholders in July. Beyond the stock related issues, the Board of Directors terminated the employment of long serving CEO Anna Gluskin. Dr. von Hofe appreciated Ms. Gluskin's efforts, and said that working in the biotechnology field comes with the realization that there will often be changes that come rather quick. He recalled his own background, when he was working for Hybridon, where he coordinated research that critically validated gene targets for novel antisense medicines, and one day during a tough financial cycle he suddenly found himself unemployed. He quickly gained work consulting for other firms, and being able to adapt to change brought fun and learning experiences that helped him later.

With Generex's stock on less stable ground, questions about the company's financial condition come into play. I asked Dr. von Hofe if he was confident that interim CEO Mark Fletcher would be able to win enough funds to funnel to Antigen Express to finish the ongoing Phase II study for AE37 with HER2/neu expressing breast cancer patients. He quickly responded "yes, and with help from Joe". Joe is Joe Moscato from Seahawk Capital based in NYC, who is playing a pivotal role in Generex's business development and financing activities. I smiled and told Dr. von Hofe that I knew Joe, and that as a shareholder I tried to help him secure votes for last week's failed reverse split. The vote was actually supported by a strong majority of the shareholders that participated in the vote, but a unique law in Delaware required that 51% of all outstanding shares needed to to vote in favor of the proposal in order for it to pass. The final tally fell just under 3% short of that daunting hurdle. Dr. von Hofe stated that funding will not be an issue and he is not concerned.

Dr. von Hofe confidently said that their "is large pharma interest" in the AE37 vaccine for HER2/neu expressing breast cancer patients. Interim results were released at the San Antonio Breast Cancer Symposium in December 2009. As a reminder about the study, two hundred disease-free, high risk, breast cancer patients who had completed standard adjuvant therapy are being enrolled and randomized to receive six monthly inoculations of either the AE37 peptide vaccine or the adjuvant GM-CSF alone to compare their ability to prevent cancer recurrence. The December interim analysis followed the first 49 patients in the AE37 group and the first 71 for the control group. At a median follow up of 13 months, there were no (0.0%) recurrences in the AE37 group of patients, 0/49, compared to 7.0%, 5/71, in the control group. Dr.von Hofe stated that he hopes more significantly powered interim results will be available by mid-2011, although a public release of those results may not be made until later that year. Often, abstracts of results are submitted months in advance to prestigious events, like SABCS, and the general public may have to wait to see what an interested pharma company can see right away. The goal is for a large pharma to join the effort in funding a large scale Phase III study.

Generex has been active in recruiting top oncology scientists to their newly formed Scientific Advisory board, and in August I had the pleasure of speaking to newly signed Dr. Craig Eagle. Dr. Eagle is the Vice President of Strategic Alliances and Partnerships for the Oncology business unit at Pfizer (PFE), and an account of our discussion can be found here. Dr. Joseph Rubinfeld, one of the original founders of Amgen (AMGN), has agreed to act as Generex's Chief Scientific Advisor, and Col. George E. Peoples, lead researcher of the United States Military Cancer Institute, is serving as a top consultant in the ongoing clinical and regulatory development of Generex's proprietary breast cancer vaccine.

In a related email exchange, Col. Peoples remarked that his "personal campaign has been to get vaccines into the adjuvant setting as opposed to the majority of trials that have been conducted in the metastatic setting". He said that "Big Pharma is not quite ready to invest given the dismal track record of previous therapeutic vaccines in the metastatic setting. Their oncology drug development strategy has always been to establish a market in metastatic patients, and then once there is a revenue stream, then go after the adjuvant market (ie, Herceptin)."

Dr. von Hofe said that he often has to remind himself to make people aware that the target for AE37 is well defined and the same as that for Herceptin, although AE37 may reach a much broader population base. Herceptin, which also zeroes in on cancer that is over-expressing HER-2/neu, can be used only in patients expressing the highest level of HER-2, or about 25 percent of breast cancer patients. In comparison, the AE37 peptide vaccine stimulates the immune system to recognize tumor cells in patients with a lower expression of HER-2, so that 75 percent of breast cancer patients may respond to Antigen's vaccine. Ovarian, prostate, lung, colon, stomach and pancreas cancers are also HER2/neu over expressing, and as such are potential targets for AE37.

Dr. von Hofe noted that Dendreon (DNDN) Corporation's approval for Provenge, the first ever therapeutic cancer vaccine approved by the FDA, ushered in a lot of new interest into the immunotherapy sector. Provenge is designed to treat metastatic prostate cancer, while Generex is gearing up for a Phase II study for AE37 in early stage prostate cancer patients. Dr. von Hofe stated that preparations are well underway, and clinical sites are currently being identified. The Phase I results for patients with prostate cancer were first announced at the 2009 ASCO Annual meeting, and are consistent with those of prior clinical trials of AE37 in patients with breast cancer. Results have shown the vaccine is targeted and effective, while causing very limited toxicity, with no patients experiencing toxicity over Grade 2.

I asked Dr. von Hofe about Apthera's E75 peptide vaccine, since I am aware that the immuno effects of this CD8 T Cell targeting vaccine are short lived. I had read previous preclinical data stating that a combined effect of E75 linked with AE37, which targets CD4 T Cells, may help E75 gain prolonged memory. Dr.von Hofe acknowledged the preliminary data suggests a combination may prove useful for E75, but that his interest is in proving AE37 is effective and safe on its own, and that AE37 is already long lasting. Also, AE37 is already the subject of a combined approach with another CD8 targeting peptide vaccine. To me, it sounds like Apthera, a private company, can figure out their problems on their own, because Generex has moved on to better opportunities.

Dr. von Hofe sat back and smiled while recalling his phone ringing and hearing of this combined peptide vaccine opportunity provided by the Mary Crowley Cancer Research Center in Dallas. Mary Crowley researchers proposed a Phase I study to assess the safety and immunological response in patients with either breast and/ or ovarian cancer with AE37 linked with GP2, a CD8 targeting T Cell peptide vaccine under research at the USMCI, and they wanted "no claims on IP". Dr. von Hofe called that a "no brainer", and said he was pleased that they recognized the potential of the AE37 vaccine. This particular study is ongoing, although Generex has no control over the slower pace of recruitment. I laughed and told Dr. von Hofe he would like more phone calls like that, and he quickly agreed.

My time with Dr. von Hofe was near complete, but I had to tell him one area I had of concern. I said that I see one problem with Antigen Express, and I asked if they were all Boston Red Sox fans? I told him that I am a Yankees fan, and he chuckled. He recalled reading a story in the newpaper of a bird in Boston that flew down and hit the head of a young girl. She was not hurt, and her named turned out to be the same as Alex Rodriguez's daughter. I mockingly protested that he would find that to be funny. It was nice to see a vaccine researcher whom I have followed and admired for so long act casual and at ease. He told me that his children were all happy when the Red Sox won the World Series, and in this case I'll make an exception to my rule. I have found a Red Sox fan that I acknowledge to be smarter than me. As he roots for the dreaded Red Sox, I root for Generex to revolutionize how early breast cancer is treated. There will be no stock exchange big enough for the company that follows in the footsteps of Herceptin and Provenge, only to potentially surpass them both.