gene therapy (viral based) plus immunotherapy with monoclonal antibody cures 4 of 5

[Lani]

mice with implanted her2+ breast cancer

Cancer Gene Ther. 2008 Jul 25. [Epub ahead of print]

Recombinant vesicular stomatitis virus targeted to Her2/neu combined with anti-CTLA4 antibody eliminates implanted mammary tumors.

Gao Y, Whitaker-Dowling P, Griffin JA, Barmada MA, Bergman I.
1Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
Vesicular stomatitis virus (VSV) is being developed for cancer therapy. We created a recombinant replicating VSV (rrVSV) that preferentially infected Her2/neu expressing breast cancer cells. We now used this rrVSV to treat macroscopic peritoneal tumor implants of a mouse mammary tumor cell line stably transfected to express Her2/neu. rrVSV therapy alone prolonged survival but did not cure any animals. rrVSV therapy combined with antibody to TGFb or antibody to IL-10 receptor (IL-10R) each produced cure in one of six animals. Strikingly, rrVSV therapy combined with anti-CTLA4 monoclonal antibody (MAb) produced cure in four of five animals. Anti-CTLA4 MAb was only effective when administered within one day of rrVSV therapy. Cure required CD4 T-cells early (<7 days) and late (>7 days) after rrVSV therapy whereas CD8 T-cells were required only late (>7 days) after rrVSV therapy. Surviving animals were resistant to re-challenge with D2F2/E2 suggesting a memory immune response. Histopathologic analysis demonstrated a dense inflammatory infiltrate of tumor nodules within days of therapy and foamy histiocytes replacing the tumor nodules 2 weeks following therapy. These studies demonstrate that targeted rrVSV combined with anti-CTLA4 MAb can eliminate established macroscopic tumor implants by eliciting an anti-tumor CD4 and CD8 T-cell immunologic response.Cancer Gene Therapy advance online publication, 25 July 2008; doi:10.1038/cgt.2008.55.
PMID: 18654610 [PubMed - as supplied by publisher

[eric]

Exciting stuff! Bring on the trial. Thanks for sharing.
Eric

[chrisy]

Damn! Yes, bring it on!

[lilyecuadorian]

Lani thanks for all these hopes that you post it everytime !!!

[julierene]

KRIKEY!!! This was just the kind of news I wanted to hear. I Was having a myserable day! I just know in my heart that gene therapy is the answer for me and my children. We are positive for the p53, Exon 10, codon 337 gene. We have Li-Fraumeni syndrome. Dr. Riberio at St. Judes told us that this is likely the kind of therapy that will come available for use in families like ours. I STILL can't WAIT!

[Lani]

be interested:

Published: Monday, 4-Aug-2008



Research funded in part by the Canadian Cancer Society may lead to a genetic screening test that could help families who are at high risk for cancer.

Researchers have found that a recently discovered genetic occurrence, called 'DNA copy number variation' (CNV), may be linked to an increased risk of cancer in people with Li-Fraumeni syndrome (LFS), a hereditary disease that already increases their susceptibility to cancer.

CNV refers to the variation in the number of copies (normally two) of a gene or sequences of DNA in the genome of an individual. The variations have been associated with susceptibility to certain diseases. This is the first genome-wide study to look at CNVs and genetic susceptibility to cancer.

Because the study also found that CNVs can be detected in the blood, the discovery paves the way for the development of a blood test to detect those people with LFS at greatest risk of developing cancer.

"One of the challenges of caring for patients with Li-Fraumeni syndrome is that it is difficult to predict when a cancer may develop," says lead researcher Dr. David Malkin, a pediatric oncologist and senior scientist at The Hospital for Sick Children. "These findings suggest that screening for CNVs in families predisposed to cancer may help identify those who are at highest risk and help us to detect any cancer early."

Heather Chappell, senior manager of Cancer Control Policy for the Canadian Cancer Society says, "Early detection is critical because we know that most cancers can be treated if they are caught early enough. This is important research that is bringing us closer to answers and options for people with Li-Fraumeni syndrome."

LFS is a rare hereditary condition that increases the risk of children and young adults developing, most commonly, breast, brain, bone and soft tissue tumours. However, the disease can be unpredictable. Different individuals within a single family can develop tumours of varying severity, at different body sites and at different ages.

Using the latest technology, the research team analyzed the DNA of healthy individuals and families affected by LFS. The team found significantly more CNVs present in LFS study subjects than in healthy subjects. They found more CNVs in LFS patients who had already developed cancer and more CNVs in the children of LFS parents. And perhaps most importantly, they found the greatest number of CNVs present in Li-Fraumeni patients who had already developed cancer compared to those who had not yet developed the disease. This finding suggests a strong link between CNV frequency and the severity of the cancers they develop. The researchers say the next step is to investigate the link between CNVs and tumour development and progression, and to determine whether similar findings are evident in other populations of cancer patients.

The Canadian Cancer Society has been a leader in research into Li-Fraumeni syndrome, providing more than $2 million to Dr. Malkin since 1995 for his studies in this field.

This study is being published in the Aug. 5, 2008 issue of the Proceedings of the National Academy of Sciences.

A survivor's story

Luana Locke isn't afraid to face her genetic destiny square in the eyes. Li-Fraumeni syndrome runs in Ms. Locke's family, which has been devastated by cancer. In fact, she is the only member of her family who has had cancer and survived. She was diagnosed with breast cancer at the age of 25. Her children have also inherited the condition.

"As a cancer survivor and mother of two kids who will likely face a cancer diagnosis in the near future, I'm happy that I've equipped myself through genetic testing and screening with the best possible tools to deal with all possible outcomes," says Ms. Locke.

It's been a difficult series of uphill battles since the diagnosis, Ms. Locke admits. Most recently, her nephew passed away on his fifth birthday earlier this year. However, she said that the "power of knowledge" has made all the difference in the early detection of her syndrome and further research means even more hope for her children.

"Whatever road LFS takes me down, I still celebrate that I'll never have to lie awake at night and ask myself those questions as a parent. I'm doing whatever I can to prevent my kids from being victimized by this disease. The questions you ask, the answers you seek give me and others like me hope - hope that the legacy of loss will, in the very near future, end

[Lani]

Proc Natl Acad Sci U S A. 2008 Aug 6. [Epub ahead of print]

Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome.

Shlien A, Tabori U, Marshall CR, Pienkowska M, Feuk L, Novokmet A, Nanda S, Druker H, Scherer SW, Malkin D.
Program in Genetics and Genome Biology, and.
DNA copy number variations (CNVs) are a significant and ubiquitous source of inherited human genetic variation. However, the importance of CNVs to cancer susceptibility and tumor progression has not yet been explored. Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited disorder characterized by a strikingly increased risk of early-onset breast cancer, sarcomas, brain tumors and other neoplasms in individuals harboring germline TP53 mutations. Known genetic determinants of LFS do not fully explain the variable clinical phenotype in affected family members. As part of a wider study of CNVs and cancer, we conducted a genome-wide profile of germline CNVs in LFS families. Here, by examining DNA from a large healthy population and an LFS cohort using high-density oligonucleotide arrays, we show that the number of CNVs per genome is well conserved in the healthy population, but strikingly enriched in these cancer-prone individuals. We found a highly significant increase in CNVs among carriers of germline TP53 mutations with a familial cancer history. Furthermore, we identified a remarkable number of genomic regions in which known cancer-related genes coincide with CNVs, in both LFS families and healthy individuals. Germline CNVs may provide a foundation that enables the more dramatic chromosomal changes characteristic of TP53-related tumors to be established. Our results suggest that screening families predisposed to cancer for CNVs may identify individuals with an abnormally high number of these events.
PMID: 18685109 [PubMed - as supplied by publisher

[fullofbeans]

Lani, thanks for this interesting post