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.

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.

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.