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Lee21 View Drop Down
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 03 2012 at 5:01pm
2011 trial report of the E75 (Neuvax) mentioned in above thread (2 year followup)

Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: From US Military Cancer Institute Clinical Trials Group Study I-01 and I-02
http://www.ncbi.nlm.nih.gov/pubmed/21989902
In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08).
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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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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 07 2012 at 9:35am
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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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 07 2012 at 7:52pm
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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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Post Options Post Options   Thanks (0) Thanks(0)   Quote 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 07 2012 at 11:57pm

DNA SEQUENCING HELPS IDENTIFY CANCER CELLS FOR IMMUNE SYSTEM ATTACK

Feb. 10, 2012 – DNA sequences from tumor cells can be used to direct the immune system to attack cancer, according to scientists at Washington University School of Medicine and the Siteman Cancer Center.

The research, in mice, appears online Feb. 8 in Nature.

The immune system relies on an intricate network of alarm bells, targets and safety brakes to determine when and what to attack. The new results suggest that scientists may now be able to combine DNA sequencing data with their knowledge of the triggers and targets that set off immune alarms to more precisely develop vaccines and other immunotherapies for cancer.

“We already have ways to identify specific targets for immunotherapy, but they are technically challenging, extremely labor-intensive and often take more than a year to complete,” says senior author Robert Schreiber, PhD, alumni professor of pathology and immunology at Washington University and co-leader of Siteman's tumor immunology program. “These difficulties have stood in the way of developing personalized immunotherapies for cancer patients, who often require immediate care for their disease. To our knowledge, this is one of the first studies to show that the faster methods provided by DNA sequencing can help. That opens up all kinds of exciting possibilities.”

Scientists have long maintained that the immune system can recognize cancer as a threat either on its own or with the help of vaccines or other immunotherapeutic treatments, which help alert the immune system to the danger posed by cancers. Once the cancer is recognized, the immune system should develop the capacity to attack growing cancer cells until either the tumor is eradicated or the immune system’s resources are exhausted.

Schreiber and his colleagues have shown that interactions between the immune system and cancer are more complex. Their theory, called cancer immunoediting, suggests that some of the mutations in tumor cells are very easy for the immune system to recognize as a threat. If the immune system detects these mutations in cancer cells, it attacks until they are destroyed.

At that point, the cancer may be eliminated. But it’s also possible that the cancer can be “edited” by the immune system, resulting in the removal of all the cells containing the critical easily recognized mutations. The remaining tumor cells can continue to grow or enter into a period of dormancy where they are not destroyed but are held in check by the immune system.

For the new study, Schreiber and his colleagues wanted to define the genetics of tumors that had yet to interact with the immune system. To do so, they induced tumors in mice with disabled immune systems. They collaborated with Washington University’s Genome Institute scientists, who sequenced the cancer cells’ genes.

“Until very recently, this work would have been impractical because of the costs involved,” Schreiber says. “But the technology has improved, and prices have come down. Now it’s possible to obtain this genetic information for a few thousand dollars instead of a million.”

To read more:

http://www.siteman.wustl.edu/contentpage.aspx?id=5745

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 miffyjones Quote  Post ReplyReply Direct Link To This Post Posted: Mar 09 2012 at 3:23am
Hi ladies - was just reading the no surrender bc site and found this article on a mutant herpes virus that sounded positive for TNBC  http://nosurrenderbreastcancerhelp.org/breastcancer101/TNBC/TNBC/Hope%20for%20TNBC.html
Lots of Love. MSmile
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 09 2012 at 11:41am
Another vaccine targeting patient population with low-intermediate Her2 expression (AE37).

Be sure to check your path report to see if your Her2 is 1+ or 2+ by IHC.  This would put you in the Her2- category but would still be part of the target population for Her2 based vaccines which seem to work best in patients with low-intermediate levels. 

Note the comment at the end of the article regarding HLA status refers to NeuVax which is dependent on a certain HLA group.

The objective for BC vaccine development is not so much prophylaxis against having BC in the first place, rather it is to prevent BC recurrence.

http://www.genomeweb.com/mdx/generex-meet-fda-about-ae37-her2-peptide-vaccine-companion-dx-path-still-unclear

Generex to Meet with FDA about AE37 HER2 Peptide Vaccine; Companion Dx Path Still Unclear


By Turna Ray

Based on promising Phase II results, Generex Biotechnology is planning to meet with the US Food and Drug Administration about its investigational cancer immunotherapy for breast patients who have tumors that express low to intermediate levels of the HER2 protein, the company said this week.

Generex's HER-2/neu peptide vaccine, called AE37, is being developed as an adjuvant therapy for the 50 percent of breast cancer patients who express low to intermediate levels of HER2, and as a result, don't have HER2 expression levels high enough to be eligible for Roche/Genentech's Herceptin, according to the company.

However, although the AE37 immunotherapeutic is for a molecularly defined patient population, Generex is not currently planning to develop the drug with a new companion diagnostic to gauge HER2 expression in the intent-to-treat patient population.

"At the moment we are not working to set up a separate diagnostic test" for AE37, Eric von Hofe, CEO of Generex subsidiary Antigen Express, told PGx Reporter. AE37 is the first product Generex is developing using Antigen Express's Ii-Key Hybrid technology platform.

"There is currently the Dako HercepTest that can be used for scoring tumor tissue HER2 1+, 2+ or 3+; with low to intermediate expressing tissue being 1+ or 2+," Von Hofe said. "There are other tests, as well, that are available that claim to be more quantitative."

Patients who end up receiving AE37 will likely be those who were initially being considered for Herceptin treatment and, as such, were already tested with one of several FDA-cleared HER2 tests and found to have low to intermediate HER2 expression. This may be one reason why Generex expects it will not have to develop a companion test for its product.

The FDA has indicated that when a drug requires the aid of a molecular diagnostic to determine which patients should receive it, the test, in most cases, must be approved by the agency. "An IVD companion diagnostic device is an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product," the FDA states in its draft companion diagnostics guidance, released last year.

The FDA-approved labeling for HercepTest notes that it is indicated "as an aid in the assessment of patients for whom Herceptin treatment is being considered." Given the rationale for how a breast cancer patient might become eligible to receive AE37, it is unclear whether the agency will require a separate FDA-cleared companion diagnostic to market the drug for a subset of the HER2 population.

Meanwhile, Dako and other firms marketing FDA-cleared HER2 tests that are supporting an additional indication for Herceptin or that are intended to be used with a new HER2-targeted therapy have had to seek approval for their tests in these new settings (PGx Reporter 6/2/2010; 2/8/2012).

The agency notes in its companion diagnostic guidance that when a test has been cleared for use with one therapeutic product "and evidence becomes available that use of the same device is essential for the safe and effective use of a different therapeutic product, the IVD companion diagnostic device labeling should be expanded through approval or clearance of a new premarket submission (PMA or 510(k) as appropriate) or PMA supplement … to include the new therapeutic product."

At the San Antonio Breast Cancer Symposium in December, Generex announced interim results from a randomized, single-blinded Phase IIb trial comparing AE37 plus granulocyte-macrophage colony-stimulating factor or GM-CSF alone in 215 breast cancer patients who had completed standard therapy, were disease-free, had node-positive disease, or had high risk node-negative disease.

At the meeting, the company reported that at a median follow up of 17 months, breast cancer patients in the AE37 arm experienced 42 percent fewer disease recurrences than those in the control arm. When researchers analyzed only patients with low HER2 expression (with an score of 1+ or 2+ by immunohistochemistry testing), study participants experienced a 49 percent reduction in recurrence compared to controls. Meanwhile, HER2 over-expressing patients saw no reduction in cancer recurrence when treated with the vaccine.

Von Hofe told PGx Reporter that the breast cancer patients enrolled in the Phase IIb study had their IHC HER2 score determined on Dako's test.

At this point in the study, researcher reported no grade 4 or 5 toxicities and found no difference between toxicity profiles of patients in the vaccine and control groups. However, when the trial was presented at SABCS, the patient cohort size was too small to yield statistically significant results, according to a statement from Antigen Express. The company plans to enroll a total of 300 women in the Phase IIb study. The primary endpoint in the study is a reduction in cancer relapse after two years.

Last week, Generex provided an update from this same trial at the Cancer Immunotherapy Summit in Boston. At a median of 22 months follow up with more than 250 patients enrolled, 89 percent of low HER2 expressing patients treated with the AE37-containing regimen experienced disease-free survival compared to around 72 percent in the control arm.

Given these results, Generex is planning to hold an end of Phase II meeting with the FDA by the middle of the year. "Immediately following that meeting, the company will begin the process for submission of a Special Protocol Assessment for a Phase III trial," the firm said in a statement.

AE37 is derived from a peptide fragment of the HER2 oncoprotein. Antigen Express's Ii-Key Hybrid technology platform, upon which AE37 is based, modifies fragments of antigens to boost their ability to stimulate CD4+ T helper cells, which are key players in the body's immune system. "Incorporating the Ii-Key modification along with tumor-associated antigens can greatly enhance the immune system's ability to recognize and destroy cancer cells bearing any of the targeted antigens, as well as increasing immunological memory," Generex explained in a statement.

According to Generex, AE37 is the only HER2-based peptide vaccine being advanced in a randomized trial. AE37's use "is not restricted to patients with a particular type of human leukocyte antigen peptide," the company noted.



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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Post Options Post Options   Thanks (0) Thanks(0)   Quote bak94 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 11 2012 at 12:12am
Hi Lee. your tumor sounds a lot like mine-3%er 1%pr her2 +1. but mine was a later stage. Did your doc recommend anti-hormonals? My doc is considering it and I am considering a second opinion, as my er is so low. Are you doing any of the vaccine trials? I would if I could find one that I qualify for! Thank you for posting all the info!
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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 11 2012 at 11:19am
Hi bak94
My oncologist mentioned some sort of endocrine therapy at my first visit but hasn't since.  I think we are waiting to see what the tumor shows at the time of surgery (I am currently still undergoing neoadjuvant therapy).  Frankly I am skeptical (see NEW MEMBERS > OPEN ACCESS thread -- there is a posting on the significance of ER expression at the low levels).
Regarding vaccine trials, I haven't really searched clinicaltrials.gov yet.  The E75 NeuVax trial is in phase 3 but there aren't any sites in Michigan (not sure about Washington, but you should follow the link shown earlier in the thread).  The AE37 trial has a site in Washington state: here is the trial info:
http://clinicaltrials.gov/ct2/show/NCT00524277?term=ae37&rank=1

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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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Post Options Post Options   Thanks (0) Thanks(0)   Quote Lee21 Quote  Post ReplyReply Direct Link To This Post Posted: Mar 13 2012 at 7:07am
Addendum
I am not sure if the clinical trial on AE37 that I referenced is the Generex study described in the news article.  It was the only AE37 trial in breast cancer that popped up and nothing came up under Generex. Anyone with additional information please post.
Also I found out that her2 is normally expressed in a variety of epithelial cells, so before you decide to go with the her2 based vaccines I would inquire about the potential of tolerance/autoimmunity - could be all theoretical.
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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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
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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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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 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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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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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
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 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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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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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.

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
2.5 cm TNBC, BRCA-, diag. 2/11, neoadj chemotherapy, uni MX, y2cm,2/16 nodes, RCBII, tumor retested 5-10%ER+,PR-,Her2-, rads, clin trial eribulin 10/11-2/12, tamox.
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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 123Donna Quote  Post ReplyReply Direct Link To This Post Posted: Mar 18 2012 at 11:01am
David,

Your analogy was excellent! Thanks
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 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 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:

DX IDC TNBC 1/15/12 @ 46; MRI 2.4cm gr3 BRCA2+ 6174delT; LMX 1/31/12 2.5cm, pT2pNO(i)pMX, lymphovascular invasion present; 2/20/12 TAC X 6; 7/2/12 Rad X 25; 9/27/2012 2nd mastectomy & BSO surgery
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