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Post Options Post Options   Thanks (0) Thanks(0)   Quote christina1961 Quote  Post ReplyReply Direct Link To This Post Posted: Nov 17 2012 at 1:43pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 30 2012 at 8:27pm

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 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Oct 09 2012 at 8:30am
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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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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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: 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 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
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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 turtle Quote  Post ReplyReply Direct Link To This Post Posted: Mar 27 2012 at 1:19pm
A new article (basic science) from Irv Weissman's group in the same vein that may be of interest:

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Post Options Post Options   Thanks (0) Thanks(0)   Quote ds21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 27 2012 at 11:38am
Nice note in Science about cancer vaccine development as a career area for scientists.  Summarizes some of the recent work and challenges.

http://sciencecareers.sciencemag.org/career_magazine/previous_issues/articles/2012_03_23/science.opms.r1200116

Of course, viewing this as a career track puts things into a longer time frame.  May be appropriate, but hope for some early results as well.

David
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 18 2012 at 11:01am
David,

Your analogy was excellent! Thanks
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Post Options Post Options   Thanks (0) Thanks(0)   Quote ds21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 18 2012 at 10:51am
Apologize for lapsing into jargon.  In his ASCO Presidential talk (http://connection.asco.org/magazine/article/id/2930/the-challenge-and-promise-of-the-genomic-era-presidential-address-of-george-sledge-md.aspx) George Sledge discusses "stupid cancers" and "smart cancers".  "Stupid cancers" have a single driving mutation like over expression of HER2 in HER2+ breast cancer.  The fact that these cancers have a single mutation creates an obvious target for treatment, and these account for many of the success stories in molecular medicine over the past decade (e.g. Herceptin for HER2+ BRCA or imatnib for CML).  In contrast, "smart cancers" (e.g. TNBC, ovarian and pancreatic cancer) have defects in their DNA replication machinery and rapidly accumulate many mutations in many genes.  This makes it harder to treat "smart cancers" with directed therapies because there are just too many genes that are messed up.  However, the presence of many "messed up" genes creates a potential opportunity for immune based treatments including vaccines.

Think of the genome as a book, and the individuals genes as chapters (OK, a very long book with about 22,000 chapters :).  Each chapter is broken into pages that in molecular biology we call exons.  Each time a cell divides, it needs to make a copy of the book so each daughter cell gets a complete copy.  In a cancer like TNBC, the copying process is messed up and errors occur ranging from single nucleotide mutations (the equivalent of a typo) to deleting exons (leaving out a page) or even shuffling exons between genes (inserting pages from one chapter into another).  After a few generations, the book gets pretty messed up with lots of nonsensical chapters, but the cell is still trying to read each chapter and turn it into a protein, only now many of these proteins are screwed up versions of what they were supposed to be.

The immune system works by recognizing proteins that are not supposed to be in your body.  In an infection, these are the proteins produced by the bacteria or virus, and the immune system reacts by killing the bacteria or the cells infected with the virus. 
The screwed up proteins produced by a cancer cell are also new to the body and in some cases, the immune system is able to recognize them and kill of the cancer cells that are making them.  The big challenge in cancer immunology is understanding how cancers evade the immune system.  With whole genome sequencing now becoming available, the hope is that we will be able to literally read the cancer genome, identify the screwed up genes in each particular cancer and then use them to specifically induce an immune response.  Still lots of work to make this happen.

David
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Post Options Post Options   Thanks (0) Thanks(0)   Quote christina1961 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 17 2012 at 8:03pm
David, Would you please explain that in layman's terminology? Does that mean that due to the nature of TNBC that vaccine therapy might have more efficacy because the TNBC doesn't appear "normal"?  I'm trying to understand, but much of this is over my head. Thanks!

Edited by christina1961 - Mar 17 2012 at 8:04pm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote ds21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 16 2012 at 8:05pm
Interesting comment that breast was not thought of as an immunogenic tumor type.  That may be true for the more common ER+ and HER2+ subtypes, but TNBC is characterized by extensive genome rearrangement creating many opportunities to express deranged genes producing aberrant and therefore immunogenic products.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 16 2012 at 1:22pm

Immunotherapy Emerges as Promising Strategy in Breast Cancer

http://www.onclive.com/conference-coverage/mbcc-2012/Immunotherapy-Emerges-as-Promising-Strategy-in-Breast-Cancer

Vaccines - one type of immunotherapy; the latest and greatest immunotherapy in metastatic melanoma is ipilimumab, an antibody directed against CTLA4, one of the immunomodulatory molecules found on T cells, functioning to suppress T cell activation.

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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 14 2012 at 10:08am
Lee,

Thanks, I'll keep this on my radar!

Donna
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 14 2012 at 10:05am
Donna,

E37 vaccine: from what I have read, this Her2 based vaccine works best for those with Her2 1+ or 2+.  It doesn't work for Her2 3+ (anyways these folks get herceptin). 
AE37 vaccine: it says it will consider Her2 1+, 2+, 3+.

From the criteria posted, it doesn't explicitly exclude recurrences, just that you have to be NED and not presently taking immunosuppressive treatments.  Both trials require node positive patients but the AE37 trial will also take high risk BC patients (TNBC).

If you are Her2 1+, like I am, at least as far as that part of the trial is concerned, you should fit the criteria.

Her2 is normally present in epithelial cells, not restricted to breast.  I think the IHC comparison is to control samples (without BC), and there is a certain amount of subjectivity.

I would keep an eye out for these trials.  Frequently they start out with restrictive criteria and when they see it works in some subsets, they will expand the inclusion criteria.  Immunotherapy when it works sometimes can produce very durable stable cures.  The mystery of our immune system.

Lee


Edited by Lee21 - Mar 14 2012 at 10:11am
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11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 14 2012 at 9:50am
Lee,

Thank you so much for all the articles you post.  From what I can tell, this new vaccine is for Her2 women or women that express Her2 with a 1 or higher.  Is that correct?  Because I'm considered Her2 negative with having an expression of 1 (0 and 1 = negative),  I wonder how effective a vaccine like this will be for those with a mild expression of Her2?  I also know I wouldn't be a candidate because of the recurrence.  There are so many trials that exclude you if you've had a recurrence (vaccine, metformin, etc).  Still, I'm very excited with research being done in the vaccine arena.  I hope we see some positive results.

Donna
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09)
11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15

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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 14 2012 at 9:16am
Here's a marketwatch press release put out by Generex (with all the caveats attached for a company's press release)
http://www.marketwatch.com/story/generex-subsidiary-antigen-express-announces-publication-of-review-showcasing-its-proprietary-therapeutic-vaccine-technology-in-the-journal-vaccine-2012-03-14
and the Vaccine paper it referenced:
http://www.ncbi.nlm.nih.gov/pubmed/22386748

So, AE37 refers to the Her2 peptide and is conjugated to li-Key/MHCII, which is then dissolved in GM-CSF. The E75 Her2 peptide is dissolved in GM-CSF and as far as I can tell, there is no additional immunoadjuvant.

Antigen Express is a subsidiary of Generex and the AE37 trial is sponsored by Antigen Express and the US Army.  So I guess it is the same trial.

There is still no peer-reviewed publication on the Generex/Antigen Express Phase 2 results except for the phase 1 data in JCO, 2008
http://www.ncbi.nlm.nih.gov/pubmed/18612158



Edited by Lee21 - Mar 14 2012 at 9:26am
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
11/9/12, clinical trial cisplatin/rucaparib, cisplatin-only arm
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