Breast Cancer Vaccine Reduces Recurrence

The following is an article published by the American Association for Cancer Research for the May edition of Cancer Discovery

Women with a history of HER2-positive breast cancer show lower rates of relapse after inoculation.

A novel hybrid vaccine reduced recurrence rates in patients with HER2-positive breast cancer by 43% after 22 months in early results of a phase IIb randomized clinical trial. Of 201 patients rendered disease free by standard treatment, those who received the vaccination had a recurrence rate of about 10.3% compared to 18% in the control group.

“We need to continue to follow these patients, but there is enough of a trend that a phase III trial is warranted,” says Elizabeth Mittendorf, MD, a surgical oncologist at MD Anderson Cancer Center in Houston and the trial's national principal investigator. The results will be presented June 4 at the 2012 Annual Meeting of the American Society of Clinical Oncology.

Antigen Express of Worcester, MA, the company producing the vaccine and a partial funder of the trial, plans to follow up with a phase III study.

The vaccine teaches CD4+ T-helper cells, immune cells that are critical in mounting a response against foreign invaders, to recognize the HER2 protein, which is expressed at some level in 75% to 80% of breast cancer tumors. The vaccine's hybrid design combines a fragment of HER2 with a novel peptide based on the immune-regulatory li protein that, in laboratory tests, was found to enhance the potency of the vaccine 250-fold.

Because the vaccine is effective in tumors with any level of HER2 expression, it may aid patients who are not eligible for targeted therapy with Herceptin (trastuzumab; Genentech) because their tumor HER2 levels are too low.

If it is eventually approved, the vaccine could be delivered in any physician's office. The ongoing trial included monthly injections for 6 months followed by boosters every 6 months for 3 years. To heighten immune response, the vaccine was paired with an immune stimulant known as granulocyte macrophage colony-stimulating factor, which was also given to patients in the control arm of the trial.

The trial targets women who are disease free after standard-of-care treatment rather than those with metastatic disease, because the vaccine was not likely to overcome aggressive and invasive tumors. “It's a paradigm shift in trial design for cancer vaccines,” says Mittendorf, who is now developing a trial giving the vaccine with chemotherapy prior to surgery to test whether inoculation during immune system reconstitution improves outcomes.

©2012 American Association for Cancer Research.

Source HERE.

ABC News Features a Report on the AE37 HER2 Cancer Vaccine

Click the word VIDEO to see the ABC news segment.

Hybrid Vaccine Demonstrates Potential to Prevent Breast Cancer Recurrence

The following is a MD Anderson News Release from 05/16/2012

Novel adjuvant therapy shows promise for women with a history of breast cancer in Phase II clinical trial

A breast cancer vaccine already shown to elicit a powerful immune response in women with varying levels of HER2 expression has the ability to improve recurrence rates and is well tolerated in an adjuvant setting, according to new research from a clinical trial led by researchers at The University of Texas MD Anderson Cancer Center.

The findings, released today, will be presented on Monday, June 4 in an oral presentation at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). It builds on previous research showing the vaccine, known as AE37, to safely and effectively raise immunity against human epidermal growth factor receptor 2 (HER2) – an oncoprotein that promotes tumor growth and is expressed to some extent in 75-80% of breast cancer tumors.

The researchers found that patients who received the vaccination had an estimated recurrence rate of 10.3% compared to 18% in the control group at a median follow up of 22 months. This represented a 43% reduction in the risk of recurrence.

“The vaccine educates the immune system to recognize HER2 as an invader,” said Elizabeth Mittendorf, M.D., assistant professor in the Department of Surgical Oncology at MD Anderson and the trial’s national principal investigator. “By introducing it into women who have had breast cancer, our goal is to instruct the immune system to immediately recognize any recurring cancer cells and orchestrate an attack.”


Building a Powerful Vaccine

The AE37 peptide vaccine used in this study is a hybrid modified to increase its potency in generating an immune response specific to cancer cells expressing HER2. It consists of a fragment of the HER2 protein (AE36), a MHC Class II epitope, linked to an Ii-Key peptide. Together, they work to stimulate a robust CD4+ T cell response, prompting the components of the immune system to seek and destroy tumor cells.

To help T cells better recognize AE37, researchers also paired the vaccine with an immune stimulant known as granulocyte/macrophage colony stimulating factor (GM-CSF). The vaccine is injected under the skin similar to a tetanus shot. The initial series consists of inoculations given monthly for six months followed by four cycles of boosters every six months.

Preventing Breast Cancer Relapse

Most experimental drugs are first evaluated in patients with metastatic disease, when tumors have undergone drastic changes, including immunoescape – a mechanism that allows tumor cells to evade elimination by the immune system. “There’s very little chance a single peptide vaccine like AE37 will overcome a tumor at this stage of disease,” said Mittendorf. “For this reason, it’s more realistic to use the vaccine to prevent recurrence rather than to treat a large mass of already present cancer cells.”

In the Phase II randomized clinical trial of 201 disease-free breast cancer patients, 103 women received the AE37 peptide plus GM-CSF adjuvantly; a control group of 98 patients received GM-CSF alone. All patients had varying levels of HER2 expression.

Results showed that the vaccine was well tolerated in the patients and toxicity was minimal; short-term side effects included redness at the injection site, flu like symptoms and bone pain. In addition to being consistent with earlier data which showed a significant immune response to the vaccine, the study also revealed how the vaccine affects recurrence rates.

The vaccine appears to prevent recurrence and work in women with any level of HER2 expression. Further, the findings draw parallels to other vaccines we now have advanced to later phase trials, Mittendorf said. MD Anderson currently has three different types of HER2-based peptide vaccines in various stages of testing and development. AE37 is the only one that targets CD4+ T cells.

“Off the Shelf” Capability

Among the benefits of a peptide-based vaccine are that it’s simple to produce and administer, and that it can be easily exported to the community compared to other available vaccines. Mittendorf noted whereas dendritic cell vaccines require patients to go to the hospital for a large blood draw that is shipped to a processing center – a complicated and expensive process – peptide vaccines can be administered to patients “off the shelf.”

The vaccine possibly offers advantages to today’s adjuvant therapies as well. “Adjuvant therapies currently used for breast cancer are taken ongoing. Otherwise, their effect to block cancer development is diminished,” said Mittendorf. “In theory, once a response is generated with immunotherapy, we can expect a longer lasting therapeutic effect without repeated dosing.

“This is an exciting time for immunotherapy as we transfer knowledge from the lab to clinic. There’s a renewed enthusiasm to manipulate the immune system therapeutically – from vaccines and antibodies to combining these modalities and improving response rates.”

The findings will be presented at ASCO by Timothy J. Vreeland, M.D., resident at Brooke Army Medical Center. The trial is funded in part by Antigen Express, the company that licenses the vaccine technology. Based on this study, Antigen Express plans to apply for a special protocol assessment from the US Food and Drug Administration to continue Phase III research needed on the vaccine.

Other researchers contributing to the study include: Diane Hale, M.D., Alan Sears, M.D. G. Travis Clifton, M.D., Nathan Shumway, D.O. and George Peoples, M.D., from Brooke Army Medical Center; Sathibalan Ponniah, Ph.D., from Uniformed Services University of the Health Sciences; and Sonia Perez, Ph.D., Michael Papamichail, M.D., Ph.D. and Alexandros Ardavanis, M.D. from Saint Savas Cancer Hospital, Cancer Immunology and Immunotherapy Center in, Athens, Greece.

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.

Novel Vaccine Reduces Risk for Breast Cancer Recurrence

The following article was written by Roxanne Nelson and appeared in Medscape on April 11, 2012.

An experimental immunotherapeutic vaccine has shown promise in the prevention of disease relapse in high-risk breast cancer patients.

A phase 2 trial, presented here at the American Association for Cancer Research 103rd Annual Meeting, has shown that women who received the AE37 HER2 peptide vaccine developed a specific immune response — an increase in circulating T cells in their blood specific for the HER2 fragment and delayed-type hypersensitivity.

In the study, more patients in the vaccine group (41 of 109 patients) than in the control group (28 of 108 patients) achieved a decrease of more than 90% in T regulatory cells, which can interfere with the immune response.

Immunotherapy is "is a nontoxic and tumor-specific therapy with a long-term memory," said Olivera Finn, PhD, distinguished professor and chair of the Department of Immunology at the University of Pittsburgh in Pennsylvania, who was not involved in the study. "The hope is that once treated it will prevent recurrence."

A number of immunotherapies, including rituximab (Rituxan) and trastuzumab (Herceptin), have already been approved and are being used as first-line treatments, she pointed out.

However, vaccines are generally used to prevent disease, noted Dr. Finn. "To intervene in a therapeutic fashion and to activate the immune system during a disease is a special challenge."

Wider Range Than Trastuzumab

With AE37, "we are aiming to stimulate the host immune system to recognize and kill cancer cells that are expressing the HER2 protein," said study author Diane F. Hale, MD, a research resident in general surgery at the Brooke Army Medical Center at Fort Sam, Houston, Texas.

The vaccine will be used in the adjuvant setting to prevent recurrence, explained Dr. Hale during a press briefing. The vaccine targets HER2, as does trastuzumab, she noted. However, "whereas only about 20% of patients are eligible for [trastuzumab], this vaccine can be used on up to 50% to 60% of patients."

AE37 is the Ii-Key hybrid of the HER2-derived peptide AE36 (776–790). Previously, a phase 1 trial showed that AE37 combined with immunoadjuvant granulocyte macrophage colony-stimulating factor (GM-CSF) demonstrated that the vaccine is safe and able to stimulate CD4+ helper T cells with HER2-specific antitumor activity. Compared with unmodified class II epitopes, the Ii-Key addition, a 4-amino-acid modification, increases vaccine potency.

Immunologic Response Observed

In this prospective, randomized, single-blinded study, Dr. Hale and colleagues compared the AE37 vaccine plus GM-CSF with GM-CSF alone in the prevention of breast cancer recurrence.

The study involved node-positive or high-risk node-negative breast cancer patients; all patients were disease free before entry into the trial, explained Dr. Hale. To date, 217 patients have been enrolled.

The women were randomized to receive AE37 plus GM-CSF or GM-CSF alone in 6 monthly intradermal inoculations. Participants had any level of HER2 expression (immunohistochemistry scores of 1+, 2+, or 3+) and specific immunologic responses to both AE36 and AE37 were evaluated.

The researchers analyzed in vitro responses using the [3H]-thymidine incorporation assay and in vivo responses using delayed-type hypersensitivity reactions. T regulatory cells were measured throughout the vaccination series.

HER2 overexpression was present in 54 patients (49.5%) who received the vaccine and in 51 (47.2%) of the control subjects (P = .783). In the vaccine group, 59 (51.4%) were estrogen-receptor positive, compared with 58 (53.7%) in the control group (P = .985).

"As we would expect, 86% of patients vaccinated with the peptide had a significant delayed-type hypersensitivity response, compared with 27% of those who were not receiving the peptide," said Dr. Hale.

The researchers also evaluated the proliferation response of cells exposed to HER2. "Intuitively, if your immune system is primed to recognize a specific peptide as foreign, it will generate a reaction in vivo and in vitro," she explained. "Patients primed to recognize HER2 as a foreign peptide demonstrated a high response. Conversely, those who did not receive the vaccine had a high nonresponse."

In vitro proliferation responses with a stimulation index of at least 2 were classified as high responders; there were 36 (33.0%) high responders in the vaccine group and 8 (7.4%) in the control group (P < .001). There were 19 (17.4%) low responders (a stimulation index of 1.5 to 2.0) in the vaccine group and 16 (14.8%) in the control group (P = .600). There were 54 (49.5%) nonresponders (a stimulation index below 1.5) in the vaccine group and 84 (77.8%) in the control group (P = .001).

The researchers also looked at T regulatory cells at baseline and after vaccination. "A large number of vaccinated patients had a decrease from baseline, leading us to believe that they had an improved immune response to the vaccine," said Dr. Hale.

Trend Toward Survival Benefit

At a median follow-up of 22 months, 90.1% of patients in the vaccine group had disease-free survival, compared with 82.6% in the control group.

"There was a trend toward survival benefit in the vaccinated patients. On subset analysis of the low-HER2-expression patients, there was an even greater benefit — an approximately 40% reduction of recurrence," said Dr. Hale.

She pointed out that survival statistics are not yet available because it is still too early in the study. The phase 2 study will continue, and there are plans to pursue a phase 3 trial.

The vaccine is being developed by Antigen Express. Eric von Hofe, PhD, president of the company, pointed out that this vaccine is much more cost effective than cellular-based therapies.

"It is meeting an unmet need," he said during the briefing, "and we are bringing it to the adjuvant setting."

American Association for Cancer Research (AACR) 103rd Annual Meeting:
Abstract LB-218. Presented April 3, 2012.

End of article from Medscape.

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.

An Update of a Phase II Trial of the HER2 Peptide AE37 Vaccine in Breast Cancer Patients To Prevent Recurrence

The following is the full abstract detailing interim results of the AE37 HER2/neu peptide vaccine that was presented at the San Antonio Breast Cancer Symposium in December:

Hale DF, Perez S, Sears AK, Clifton GT, Vreeland TJ, Holmes JP, Ardavanis A, Pistamaltzian N, Rellias G, Ponniah S, Papamichail M, Peoples GE, Mittendorf EA. Brooke Army Medical Center, Ft. Sam Houston, TX; Saint Savas Cancer Hospital, Athens, Greece; Naval Medical Center San Diego, San Diego, CA; Uniformed Services University of the Health Sciences, USMCI, Bethesda, MD; UT M.D. Anderson Cancer Center, Houston, TX

Introduction

AE37 is the Ii-Key hybrid of the HER2-derived peptide AE36 (HER2:776-790). A phase I trial administering AE37 with the immunoadjuvant GM-CSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T-cells with HER2-specific anti-tumor activity. Here we present an update of our prospective, randomized, single-blinded, phase II trial of the AE37 vaccine for the prevention of breast cancer recurrence in disease-free, high risk patients.

Methods

After completion of standard therapy, disease-free, node positive or high risk node negative breast cancer patients were randomized to receive either AE37+GM-CSF (vaccine) or GM-CSF alone (control) in six monthly intradermal inoculations. Patients were enrolled with any level of HER2 expression, (IHC 1+ 2+ or 3+). Specific immunologic responses to both AE36 and AE37 were evaluated in all patients at pre-determined intervals: before (RO), mid-series (R3), upon completion (R6), and at six (RC6) and 12 (RC12) months after completion of the vaccine series. In vitro responses were measured using the [3H]-thymidine incorporation assay and in vivo responses using delayed-type hypersensitivity (DTH) reactions. The trial's primary endpoint is disease recurrence.

Results

To date, 215 patients have enrolled (vaccine=92, control=123). 99% of local and systemic toxicities were ≤grade 2 or less. There were no grade 4-5 local or systemic toxicities and no difference between toxicity profiles of vaccine and control groups. Vaccine patients exhibited a statistically significant increase from baseline in AE36 and AE37 proliferative responses at each time point, including maintenance of this response up to 12 months post-vaccination (AE36 (cpm):

R0=0, R3=1335, R6=1242, RC6=1586, RC12=1360; AE37: R0=0, R3=2859, R6=2300, RC6=3235, RC12=3279, p<0.001) while there have been no proliferative changes for control patients (AE36: R0=91, R3=95, R6=97, RC6=126, RC12=48; AE37: R0=291, R3=399, R6=319, RC6=103, RC12=0). Vaccine patients also had statistically significant increases in DTH reactions to both AE36 and AE37 (AE36 (mm): R0=0, R6=15, RC6=15, RC12=15; AE37: R0=0, R6=24, RC6=17, RC12=20 p=<0.001) while controls had no response (AE36: R0, R6, RC6, RC12=0; AE37: R0, R6, RC6, RC12=0).

With a median follow up of 17 months, breast cancer recurrences were reduced by 42% in vaccine patients compared to control patients (7.6% vs. 13.2%, p=0.15). In an analysis of patients with low HER2 expression (IHC 1 or 2+), vaccine patients experienced a 49% reduction in recurrence compared to controls (9.5% vs. 18.6%, p=0.16) with no reduction seen in HER2 over-expressing patients (6.0% vs. 7.9%, p=0.49).

Conclusions

The AE37 vaccine is safe and well tolerated with only mild toxicity, which is attributable to the GM-CSF immunoadjuvant. The AE37 vaccine elicits strong peptide specific in-vivo and ex-vivo immune responses, which are maintained for 12 months after completion of the vaccine series. While the number of recurrences are still low, the recurrence rate appears to decrease in vaccinated patients. Administration of the AE37 vaccine may reduce the risk of breast cancer recurrence with the greatest benefit in patients with low levels of HER2 expression.

The poster, which accompanies the abstract, details further information of the interim analysis. Here's some of findings,

AE37 is the Ii-Key hybrid of the HER2-derived peptide AE36 (HER2:776-790). A phase I trial administering AE37 with the immunoadjuvant GM-CSF demonstrated vaccine capable of stimulating CD4+helper T-cells with HER2-specific anti-tumor activity.
Here we present an update of our prospective, randomized, single-blinded, phase II trial of the AE37 + GM-CSF vs. GM-CSF alone for the prevention of breast
cancer recurrence in disease-free, high risk patients.

To date, 247 patients have enrolled (vaccine=103, control=144).

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

Vaccine patients exhibited a statistically significant increase baseline in AE36 and AE37 proliferative responses at each time point, including maintenance of this response up to 12 months post-vaccination while there have been no proliferative changes for control patients.

Vaccine patients also had statistically significant increases in DTH reactions to both AE36 and AE37 while controls had no response.

With a median follow up of 22 months disease free survival (DFS) was improved from 82% to 89.7% in the vaccinated patients compared to controls corresponding to a
43% reduction in recurrences.

In subset analyses by HER2 expression levels, DFS was improved from 71.9% to 88.6% in vaccinated patients with low HER2 expression (IHC 1+ or 2+) compared to controls
corresponding to a 46% reduction in recurrences. There was no improvement in DFS for patients with HER2 over-expressing (IHC 3+ or FISH positive) tumors comparing to controls.

The AE37 vaccine is safe and well tolerated with only mild toxicity, which is attributable to the GM-CSF immunoadjuvant. The AE37 vaccine elicits strong peptide specific in-vivo and ex-vivo immune responses, which are maintained for 12 months after completion ofthe vaccine series. While the number of recurrences are
still low the reactions the recurrence rate is decreased in vaccinated
patients. Administration of the AE37 vaccine may reduce the risk of breast cancer recurrence with the greatest benefit in patients with low levels of HER2 expression.

Recent Advances in Understanding the Immune System and the Role of T Helper Cells

Utilizing a modulated immune response mediated by T helper cells, Antigen Express technology focuses on a class of lymphocytes that plays a multifaceted role in the immune system, both enhancing and suppressing immune response. In this podcast, Eric von Hofe, Ph.D., President of Antigen Express, takes a look at advancements in immunotherapy and their studies investigating the efficacy and safety of these technology platforms.

Listen to this podcast from Dr von Hofe here.