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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Apr 02 2012 at 9:41pm
2 abstracts from the AACR ongoing annual meeting on the AE37 BC vaccine trial:

One is a news snippert -- the actual abstract hasn't been released yet due to news embargo:
http://www.newswise.com/articles/peptide-vaccine-stimulates-immune-response-in-patients-with-breast-cancer?ret=/articles/list&category=medicine&page=1&search[status]=3&search[sort]=date+desc&search[section]=10&search[has_multimedia]=
http://www.philly.com/philly/health/HealthDay663304_20120402_Early_Study_Hints_That_Breast_Cancer_Vaccine_Might_Work.html?cmpid=138896554

The second is posted here:< name="aspnet" method="post" ="AbstractPrintView.aspx?mID=2898&sKey=b83a260c-41db-47f8-b1c1-8c14e4f32b1f&cKey=bb3b785a-0ed1-484d-9b91-ebcf4ba8b52f" id="aspnet">


Presentation Abstract



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
Presentation Time: Monday, Apr 02, 2012, 1:00 PM - 5:00 PM
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
Abstract Body: Introduction:
We are conducting a Phase II clinical trial of 2 HER2 peptide vaccines, GP2 (MHC Class I restricted) and AE37 (MHC Class II restricted), for the prevention of breast cancer (BCa) recurrence in disease-free, high risk patients (pts). We present analysis of T cell populations in trial patients at the time of enrollment and differences based on time since chemotherapy. We describe a “reconstitution” of the immune system after immunosuppressive chemotherapy.
Methods:
After completion of standard therapy, disease-free, BCa pts were enrolled. Demographic data was collected. Blood was collected prior to administration of their first vaccine. Peripheral blood mononuclear cells from 50 pts were isolated and evaluated for CD8+, CD4+CD8+, CD4-CD8- and CD4+ T cell populations. T cell proliferation responses were measured in patients of both arms of the trial; generically with FluM-specific CD8 cells (HLA-A2:Ig dimer assay) in the GP2 arm (n=58), and then with proliferation response to AE36 and AE37 in the AE37 arm (n=85). Linear regression analyses evaluated the relationship between time from chemotherapy and each T cell population. Immune responses of pts enrolled less than one year from chemotherapy (<1yr group) were then compared with those enrolled more than one year from chemotherapy (>1yr group) using a t-test.
Results:
Chemotherapy regimens were determined by the treating oncologist and consisted primarily of anthracycline-based regimens with a taxane. Regression analysis revealed a significant correlation between time from chemotherapy and both CD4+ and CD8+ Tcell counts (R= .433, p=0.015 and R=.439, p=.014, respectively). Total T cell, CD4-CD8- and CD4+CD8+ populations, however, did not significantly correlate with increased time from chemotherapy (R=.28, p=0.128, R=.068, p=.715 and R=.058, p=.755, respectively). Comparison between the <1yr group and the >1yr group in the GP2 arm (n=43 and n=15) for FluM-specific CD8 cells revealed a non-significant increase in immune response in the >1yr group (2.74 vs 3.57, p=0.15). A similar comparison in the AE37 arm (n=56 <1yr, n=29 >1yr) revealed increased proliferation in the >1yr group (AE36: 1110 vs 2167, p=0.034, AE37: 983 vs 2179, p=0.001). There were no significant differences between the >1yr and <1yr groups of either arm with respect to AJCC stage, HER2 status, or ER/PR status.
Conclusion:
Immune reconstitution is emerging as an important concept in the care of cancer pts, especially in immunotherapy, where enhancing a pts’ immune response is the key to success. We have shown that increased time from chemotherapy correlates with reconstitution of the immune system, manifest by increased CD8+ and CD4+ T cell counts and increased in vitro immune responses. Future analysis will determine if increased immune reconstitution, portends a better response to cancer vaccines and improved outcomes.



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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Apr 03 2012 at 11:41am


Presentation Abstract



Abstract Number: LB-218
Presentation Title: Immune response assessment in a phase II trial of AE37 HER2 peptide vaccine
Presentation Time: Tuesday, Apr 03, 2012, 8:00 AM -12:00 PM
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
Abstract Body: Introduction:
AE37 is the Ii-Key hybrid of the HER2 derived peptide AE36 (776-790). A phase I trial administering AE37 with the immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T cells with HER2 specific anti-tumor activity. Here we present an analysis of our immunologic testing of our prospective, randomized, single-blinded, phase II trial of the AE37+GMCSF vs. GMCSF alone for the prevention of breast cancer recurrence.
Methods:
After completion of indicated standard therapy; disease-free, node positive or high risk node negative breast cancer patients were randomized to receive either AE37+GMCSF (VG) or GMCSF (CG) in 6 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 vitro responses were measured using [3H]-thymidine incorporation assay and in vivo responses using delayed-type hypersensitivity (DTH) reactions. T regulatory cells (Tregs) were measured throughout vaccination series. Data was analyzed using Pearson chi-squared tests.
Results:
To date 217 patients have enrolled (VG=109, CG=108). HER2 over-expression was present in 54 (49.5%) VG and 51 (47.2%) CG, p=0.783. VG had 59 (51.4%) ER positive and CG had 58 (53.7%, p=0.985).
The in vitro proliferation responses with a stimulation index (SI) ≥2 were classified as high responders VG 36 (33.0%) vs CG 8 (7.4%, p<0.001 ), SI 1.5-2 were classified as low responders VG 19 (17.4%) vs CG 16 (14.8%, p=0.600) or SI <1.5 as non responders VG 54(49.5%) vs CG 84(77.8%, p<0.001).
The in vivo DTH reactions measured in 149 (VG n=86, CG n=63) were stratified as responders with ≥5mm (VG 74(86.0%) vs CG 17(27.0%) p<0.0001) or non responders with <5mm (VG 12 (14.0%) vs CG 46(73.0%) p<0.001).
Tregs responses were measured in 107 patients (VG n=56, CG=51) and categorized according to percent change from pre-vaccination baseline as an increase >110% (5(8.9%) VG vs 10 (19.6%) CG, p=0.112), no change 90-110% (10 (17.9%) VG vs 13 (25.5%) CG, p=0.337), or decrease <90% (41 (73.2%) VG vs 28 (54.9%), p=0.048).
Conclusion:
VG patients had significant immunologic responses compared to CG. VG had a statistical decrease in Tregs compared to CG. Monitoring immunologic tests and Tregs throughout the vaccination process may stratify patients into responders and non responders and thus assist in identifying patients that will have recurrence.




Edited by Lee21 - Apr 03 2012 at 11:42am
12/9/11 @59,IDC,grade3, TNBC,3cm(MRI),SLNB0,stage IIA, BRCA1 variant
1/30/12 DD AC-T, 6/7/12 Lumpectomy, ypT1b(0.8 cm), 7/9/12 Rads x 30
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: May 17 2012 at 8:49pm
Hybrid vaccine demonstrates potential to prevent breast cancer recurrence

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) A– 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– 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– a complicated and expensive process A– 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 A– 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.

Contact: Laura Sussman
lsussman@mdanderson.org
713-745-2457
University of Texas M. D. Anderson Cancer Center

http://www.breakthroughdigest.com/medical-news/hybrid-vaccine-demonstrates-potential-to-prevent-breast-cancer-recurrence/

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: May 19 2012 at 12:27pm
Established Cancer Vaccine Works Better In Tandem With FDA-Approved Kidney Transplant Drug
A team from the Perelman School of Medicine and the Abramson Family Cancer Research Institute at the University of Pennsylvania found that the FDA-approved drug daclizumab improved the survival of breast cancer patients taking a cancervaccine by 30 percent, compared to those patients not taking daclizumab. This proof-of-concept study is published this week in Science Translational Medicine. Senior authors of the study are Robert H. Vonderheide, MD, DPhil, associate professor of Medicine, and James Riley, PhD, associate professor of Microbiology. 

The team proposed that daclizumab, already used for kidney transplantation, would be effective in depleting regulatory T cells (Tregs) and restoring the immune system's ability to fight tumors. Tregs are an important population of white blood cells that help turn off the immune system when the system's job is done. Cancer immunotherapy has been used for the last decade, but researchers have been trying to tweak the system to get immune cells to react more robustly to destroy tumors. In time, though, the body slams on the breaks, rendering vaccines less effective. 

Tumor cells exploit Tregs, drawing them to the tumor area. Tregs are essentially hijacked by the tumor, surrounding even the smallest tumors in a protective shell, preventing other tumor-fighting white blood cells from getting to tumor cells at the core. 

Tregs rely on a particular protein, called IL-2, for most of their functions. Daclizumab is an antibody that binds to the CD25 receptor on the surface of Tregs to which IL-2 binds. Tregs are deprived of IL-2 in the presence of daclizumab since it binds to the CD25 receptor instead of IL-2. But rather than causing Tregs to die, using normal lymphocytes from a biobank at Penn run by Riley, the team found the lack of IL-2 forces Tregs to convert into normal T cells that no longer surround the tumor. Once this happens, the tumor-fighting immune cells might be able to make their way into the tumor. 

To bring this idea to patients, the team then designed a clinical trial, which was directed by co-author Kevin Fox, MD, professor of Medicine, and administered daclizumab to 10 patients with metastatic breast cancer prior to giving them an experimental breast cancer vaccine developed and manufactured at Penn. 

"Daclizumab worked incredibly well," says Vonderheide. There were no detectible side effects, and the T-cell conversion in the patients on daclizumab lasted two months. Their tumors didn't shrink, but in six out of the 10 patients the tumors did stop growing. And, the daclizumab patients had an increased survival of about seven months compared to patients on the cancer vaccine alone. 

To date, says Vonderheide, all previous attempts to eliminate Tregs have been toxic and short-lived, but the effects of daclizumab were observed to be rapid, prolonged, and consistent. 

"Although we tested our approach in patients with breast cancer, we know that Tregs can block the immune response against most human cancers," says Vonderheide. "Drugs like daclizumab might be useful for most cancer patients, especially those receiving other types of immune therapy. Although Tregs do help prevent autoimmunity, we did not observe an autoimmune response because we did not convert all Tregs in the body, only those cells that seem to protect the tumor. Going after only some, but not all Tregs, we believe, was an important and unique aspect of our study. Although there is a great deal of work to do to confirm our findings, we believe this will have major implications for cancer vaccine regimens in other types of cancer." 

Although daclizumab is not currently available from its manufacturer, a second trial with a related FDA-approved drug is slated to open for enrollment at Penn this summer for patients with metastatic breast cancer. 

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Sep 25 2012 at 9:21pm
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U.S. Army surgeons exhibited new research findings in two poster presentations 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. 

More complications for Crohn's Disease patients following emergency colorectal surgery 

Also presented today at Clinical Congress, the poster "A NSQIP Evaluation of Practice Patterns and Outcomes Following Surgery for Anorectal Abscess and Fistula in Patients with and without Crohn's Disease," discussed outcomes for CD patients following emergency surgery for anorectal abscess and fistula. 

Lt. Col. Scott R. Steele, M.D., based at Madigan Army Medical Center, presented a retrospective review of medical data from the American College of Surgeons National Surgical Quality Improvement Program database (ACS-NSQIP, 2005-2010) to calculate 30-day outcomes of patients with and without underlying CD. 

"People with Crohn's Disease are known for having a more aggressive form of anorectal disease and this study affirms that," said Steele. "Study results also showed that complications following emergency colorectal procedures were more prominent in patients with CD than patients without the disease." 

The study data included 7,218 patients who met inclusion criteria with a mean age of 45 years. Even though the majority of patients studied were male (64 percent), CD patients presenting with anorectal disease were younger and more frequently female. 

Capt. Marlin Wayne Causey, M.D., Capt. Dan Nelson, D.O., Lt. Col. Eric K. Johnson, M.D., Justin A. Maykel, M.D., Brad Davis, M.D., David E. Rivadeneira, M.D., and Brad Champagne, M.D., also participated in the study. 
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In Mice, Combining Cancer Vaccine and Low-Dose Anti-Angiogenesis Drug Shows Promise against Breast Cancer

A combination of a therapeutic cancer vaccine and low doses of a drug that blocks tumor blood vessel growth (an angiogenesis inhibitor) may be an effective treatment for breast cancer, according to a study in mice.

In two different mouse models of breast cancer, the combination treatment shrank tumors more than either treatment alone, and in one model it also improved survival.

Dr. Rakesh Jain and his colleagues from Massachusetts General Hospital and Harvard Medical School published the findings October 8 in the Proceedings of the National Academy of Sciences.

Evidence from both human and animal studies has suggested that lower doses of angiogenesis inhibitors can “normalize” tumor blood vessels, making them less leaky and more functional—an effect that could improve the delivery of other therapies. And several recent studies suggest that abnormal tumor vasculature “fosters an immunosuppressive [tumor] microenvironment” that may help tumors evade detection or attack by the immune system, the researchers wrote. If so, they continued, normalizing the vasculature could improve vaccine efficacy.

They tested low and high doses of the angiogenesis inhibitor DC101 alone or in combination with a therapeutic vaccine in different mouse models of breast cancer. Based on previous research, they explained, “the schedule of combination treatment…was designed to synchronize vascular normalization and T-cell activation [by the vaccine].”

The researchers also looked for clues that could explain why the combination of the vaccine and low-dose angiogenesis inhibitor was more effective. Compared with blood vessels in mice that received higher doses of DC101 and the vaccine, they found that those in mice treated with lower doses of DC101 and the vaccine were more stable and more evenly distributed throughout the tumor. This appeared to increase the infiltration of immune cells into the tumor following vaccination and to encourage a stronger immune response to the tumor.

According to Dr. James Gulley of NCI’s Center for Cancer Research (CCR), the study findings are consistent with recent research conducted by Dr. Benedetto Farsaci in CCR’s Laboratory of Tumor Immunology and Biology, involving a therapeutic cancer vaccine in combination with sunitinib (Sutent).

Clinical trials to test a therapeutic vaccine with low doses of an angiogenesis inhibitor in women with breast cancer are in the early planning stages, Dr. Jain said.

http://www.cancer.gov/ncicancerbulletin/103012/page3#d

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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Dec 01 2012 at 12:44pm

Early efficacy analysis of the AE37 vaccine in patients with HER2 low-expressing and triple-negative breast cancer.


Sub-category:
Triple-negative

Category:
Systemic Therapy

Meeting:
2012 Breast Cancer Symposium

Session Type and Session Title:
Poster Discussion Session B 
General Poster Session B

Abstract No:
109

Citation:
J Clin Oncol 30, 2012 (suppl 27; abstr 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


Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^) here and in the printed Proceedings.

Abstract Disclosures

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 reductionConclusions: 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.


Presented at the 2012 ASCO Breast Cancer Symposium.  A phase 3 trial is supposed to be in the works.

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Lee,

Thanks for posting this information.  "The DFS rate in the VG of TNBC patients is 83.3% vs 47.6% in the CG (p=.23), a 68% risk reduction."  Promising indeed.  Hope they move to Phase III trials very soon or we see this become available adjuvant therapy for all TNBC.  I'd take a 68% risk reduction any day.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jan 08 2013 at 7:30pm

Emerging Vaccines Take Aim at Preventing Recurrent Breast Cancer

By Joe Munch

Graphic: Disease-free survival
Kaplan-Meier plots depict disease-free survival for patients in the phase I and II trials of the E75 vaccine. Following standard treatment for breast cancer, patients were vaccinated with E75 and granulocyte-macrophage colony-stimulating factor or remained unvaccinated (controls).

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.”

FURTHER READING

Mittendorf EA, Alatrash G, Xiao H, et al. Breast cancer vaccines: ongoing National Cancer Institute–registered clinical trials. Expert Rev Vaccines 2011;10:755–774.

For more information, call Dr. Elizabeth Mittendorf at 713-792-2362 or Dr. Jennifer Litton at 713-792-2817.

http://www2.mdanderson.org/depts/oncolog/articles/13/1-jan/1-13-1.html

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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: May 24 2013 at 2:46pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Jul 13 2013 at 12:24pm
Why cancer vaccines haven't worked

A vaccine that launches an immune attack on cancer cells has so far proved to be better in theory than in practice, and researchers may finally understand why.

Willem Overwijk, Ph.D., associate professor in MD Anderson’s Department of Melanoma Medical Oncology, and his colleagues found that a mineral oil known as incomplete Freund’s adjuvant (IFA), added to cancer vaccines to stimulate the immune system, might do too good a job.

The vaccine effectively activates T cells, which are supposed to target cancer cells and destroy them — shrinking tumors and preventing them from spreading to other locations and seeding new growths. But because IFA is not biodegradable, it remains under the skin at the injection site, acting as an irresistible bait for the T cells.

“Vaccines stimulate production of T cells primed to attack the target cancer, and there are many T cells in the bloodstream after vaccination. We found that only a few get to the tumor while many more are stuck at, or double back to, the vaccination site,” Overwijk says.

Essentially, he says, the vaccine competes with the tumor for the attention of the immune cells. The vaccine, because of its powerful ability to stimulate the defensive cells, tends to be more dominant. “That explains why we find nice levels of T cells in blood after vaccination but no correlation with a response against tumors in patients,” Overwijk says.

Engineering flaw discovered 

The oil may not be the only saboteur. It’s also possible that the tumor itself sends out inhibitory factors that either disguise the tumor from immune sentries, or discourage T cells from venturing too close. But if oil is part of the problem, then switching to a less persistent formulation may improve responses to cancer vaccines.

Meanwhile, Overwijk and his colleagues infer that a possible solution would be to reduce the size and persistence of vaccine “depots” at the injection site. They’ve tested a vaccine based on a biodegradable saline solution instead of IFA, and found antigens cleared more quickly but did not spark the desired T cell response. Adding co-stimulating agents to the saline vaccine corrected this effect, allowing more T cells to attack the tumor and leaving few at the injection site.

“It’s an engineering flaw in those vaccines that we didn’t appreciate until now,” Overwijk says. “Fortunately, our results also directly instruct us how to design new, more powerful vaccine formulas for treating people with cancer.”

Reported in the March 3, 2013, online edition of Nature Medicine


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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Aug 27 2013 at 7:10pm
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Post Options Post Options   Thanks (1) Thanks(1)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Feb 13 2014 at 11:17pm
A VACCINE that can prevent breast cancer returning has been developed by Australian scientists and could be on the market within five to ten years.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote sabinecalifornia Quote  Post ReplyReply Direct Link To This Post Posted: Feb 14 2014 at 9:51am
I wish it would be available sooner.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Apr 28 2014 at 8:51pm
Update on the E75 (NeuVax) Vaccine:

Edited by 123Donna - Apr 30 2014 at 8:22am
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We'll have to keep an eye on this research and Phase 1 Clinical Trials.

Promising new approach targets cancer protein to slow tumor growth

Sometimes a full-on assault isn't the best approach when dealing with a powerful enemy. A more effective approach, in the long run, may be to target the support system replenishing the supplies that keep your foe strong and ready for battle.

A group of researchers from the Abramson Cancer Center and the Perelman School of Medicine at the University of Pennsylvania is pursuing this strategy by employing a novel DNA vaccine to kill cancer, not by attacking tumor cells, but targeting the blood vessels that keep them alive. The vaccine also indirectly creates an immune response to the tumor itself, amplifying the attack by a phenomenon called epitope spreading. The results of the study were published this month in the Journal of Clinical Investigation.

Previous studies have targeted tumor angiogenesis (the formation of new blood vessels that feed the tumor cells). However, this approach can also interfere with normal processes involved in wound healing and development. Penn researchers avoided this pitfall by designing a DNA vaccine that specifically targets TEM1 (tumor endothelial marker 1), a protein that is overexpressed in tumors and poorly expressed in normal tissues.

"We demonstrated that by targeting TEM1, our vaccine can decrease tumor vascularization, increase hypoxia of the tumor and reduce tumor growth," says Andrea Facciabene, PhD, research assistant professor of Obstetrics and Gynecology and a faculty member in the Ovarian Cancer Research Center at Penn Medicine. "Our results confirm that we were directly targeting the tumor vasculature and also indirectly killing tumor cells through epitope spreading."

The Penn team injected mice with a DNA fusion vaccine called TEM1-TT, created by fusing TEM1 complementary DNA with a fragment of the tetanus toxoid (TT). In mouse models of three cancer types (breast, colon, and cervical), tumor formation was delayed or prevented in mice vaccinated with the TEM1-TT DNA vaccine. Specifically, they found that the mouse tumors had suppressed growth, decreased tumor vessel formation, and increased infiltration of immune cells into tumors.

The researchers found that the DNA vaccine, after killing the endothelial cells that make up the tumor vessels (vasculature), also resulted in epitope spreading, meaning that the immune cells of the mice gathered pieces of dead tumor cells (due to hypoxia) to create a secondary immune response against the tumor itself. The vaccine induced specific T cells to fight other tumor cells expression other proteins, in addition to TEM1, thus increasing its therapeutic efficacy.

The new DNA vaccine approach to fight cancer is showing great potential compared to previous studies that focused on tumor cells rather than the blood vessels that allow tumor cells to thrive.

"Until now there have been a lot of clinical trials using DNA vaccines to target tumors themselves, but unfortunately the results have been disappointing," Facciabene notes. "This is a different approach which should heighten optimism for cancer vaccines in general. Moreover, based on what we've seen in our mouse studies, this vaccine doesn't seem to show any significant side effects."

The prevalence of TEM1 in a wide range of tumor types coupled with its scarcity in normal vessels makes it a suitable target both for a prophylactic defense against cancer and a complement to other therapies such as radiotherapy and chemotherapy. "Using this vaccine simultaneously with radiation may eventually have a double synergy," Facciabene says. "Both treatments affect the tumor endothelium, radiotherapy could help the phenomenon of epitope spreading induced by the TEM1-TT vaccine." In addition to ongoing pre-clinical work with human TEM1, Facciabene and colleagues are planning to move on to Phase I human clinical trials.

The authors suggest that TEM1 may also be an excellent target as a prophylactic cancer vaccine for individuals that have a high risk of developing ovarian cancer, such as carriers of the BRCA1/2 mutations, predominant in breast and ovarian cancer. Research to develop those types of strategies is a key goal of Penn's Basser Research Center for BRCA. As a bonafide vaccine, TEM-TT DNA vaccine generates a memory immune response, which Facciabene says is an ideal attribute for high risk populations.

http://www.medicalnewstoday.com/releases/276019.php?tw

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First Breast Cancer Vaccine Passes Phase 1 Clinical Trials

Doctors at the University of Arkansas for Medical Sciences (UAMS) are done with a Phase I breast cancer vaccine trial.

The breast cancer vaccine induced antibody responses in the “small group of participants who received five injections of the vaccine” in 23 weeks. Consequently, clinical vaccine collaborators Dr .Thomas Kieber-Emmons, PhD, and Dr. Laura Hutchins, M.D., are happy with the trial’s success. Hutchins selected participants for the Phase I trial. Kieber-Emmons developed the vaccine at UAMS.

The trial at UAMS is the first time a breast cancer vaccine has been tested in humans outside of US military families. The human trial trumps research by others—from Dr. Vincent Tuohy in Cleveland to the United States Army. In October 2013, Tuohy found breast cancer vaccine success in lab mice. Tuohy needed funding for a Phase I trial. UAMS received its funding from a Clinical Translational Award from the Department of Defense Breast Cancer Program.

In 2012, the United States Army’s Cancer Vaccine Development Program was set to begin Phase III trials in the beginning of 2013. You can read more about its program here.

Kieber-Emmons’ peptide vaccine was designed to “trigger an immune response that destroys the cancer cells. The peptide (a computer generated chemical compound) “mimics carbohydrates that are attached to the cancer cells and tricks the immune system into attacking those carbohydrates” (UAMS).

Phase II of the trial begins in “the next few months to examine if the vaccine improves the efficacy of preoperative chemotherapy” (UAMS). In other words, Phase II seeks to determine whether or not the “combination of vaccine and standard chemotherapy improves the benefit from preoperative therapy.”

http://www.vaccinews.net/2014/05/first-breast-cancer-vaccine-passes-phase-i-clinical-trials/

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