truly exciting her2 bc research finding--still in micem but hopeful!!!

[Lani]

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

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response.

Stagg J, Sharkey J, Pommey S, Young R, Takeda K, Yagita H, Johnstone RW, Smyth MJ.
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia;
Despite the development of human epidermal growth factor receptor-2 (ErbB-2/HER2)-targeted therapies, there remains an unmet medical need for breast cancer patients with ErbB-2 overexpression. We investigated the therapeutic activity of an agonist mAb to mouse tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 (DR5) against ErbB2-driven breast cancer. Established tumors in BALB/c transgenic mice expressing a constitutively active ErbB-2/neuT were treated with anti-DR5 mAb and/or anti-ErbB-2 mAb and monitored for tumor progression. Treatment with anti-DR5 or anti-ErbB2 mAb as single agents significantly delayed tumor growth, although all tumors eventually progressed. Remarkably, treatment with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in a majority of mice. In vivo blockade of CD11b(+) cells, but not natural killer cell depletion, significantly abrogated the early antitumor response. Notably, depletion of CD8(+) T cells provoked primary and secondary tumor relapse, revealing the induction of antitumor immunity by the combination treatment. Combined therapy with anti-DR5 and anti-ErbB-2 mAbs further significantly suppressed the growth of advanced spontaneous tumors in ErbB-2/neuT transgenic mice, even when treatment was delayed until tumors were palpable. We thus demonstrated that the combination of anti-DR5 and anti-ErbB2 mAbs might be an effective form of treatment for ErbB-2-overexpressing breast cancer.
PMID: 18838682 [PubMed - as supplied by publisher]

[Lani]

an antibody against TRAIL ligand (RANKl) is nearing FDA approval...have no idea if TRAIL receptor 2 mAbs are being tested/used. Will research...

[Lani]

one is AMGEN who make denosumab, mAb vs RANKL, who have 5 active trials


A Phase 1b/2 Study of AMG 655 in Combination With Paclitaxel and Carboplatin for the First-Line Treatment of Advanced Non-Small Cell Lung Cancer




Phase II, Phase I




20060295
NCT00534027







2.
Phase 1b/2 Study of AMG 655 With mFOLFOX6 and Bevacizumab for First-Line Metastatic Colorectal Cancer




Phase II, Phase I




Active


18 and over



20060464
NCT00625651







3.
Phase 1b/2 Study of AMG 655 With Doxorubicin for the First-Line Treatment of Unresectable Soft Tissue Sarcoma





Phase II, Phase I



Pharmaceutical / Industry


20060324
NCT00626704







4.
A Study of AMG 655 or AMG 479 in Combination With Gemcitabine for Treatment of Metastatic Pancreatic Cancer





Phase II, Phase I







20060323
NCT00630552







5.
AMG 655/Panitumumab Combination Metastatic Colorectal Cancer Study

[Lani]

Clinical Experience with Agonistic Death-Receptor Monoclonal Antibodies

Presently there are several agonistic monoclonal antibodies against DR4 and DR5; our humanized antibody against DR5 (CS-1008), the Human Genome Science (HGS) fully human antibodies (HGS-ETR1 anti-DR4, HGS-ETR2 and HGS-TR2J anti-DR5), the Genentech Apomab fully human anti-DR5 antibody,[18] the Amgen AMG 655[19] and Novartis LBY135[20] anti-DR5 antibodies. The results of a Phase I trial of mapatumumab (HGS-ETR-1) have been reported. This dose-escalation trial utilized doses of 0.01–10 mg/kg intravenously and 10 mg/kg every 2 weeks, which was safely tolerated in 11 patients with a plasma half-life of 18.8 days. Preliminary reports of Phase I trials of anti-DR5 monoclonal antibodies in patients with advanced metastatic cancer have been reported.[6,18] These trials have demonstrated that these agents are well-tolerated, have attractive pharmacokinetics with plasma half-life of less than 12 days and limited single agent antitumor efficacy with prolonged stable disease as the best antitumor effect. A Phase II trial of mapatumumab in patients with advanced non-Hodgkin's lymphoma has recently reported objective response in three out of 40 patients (8%), all of whom had follicular lymphoma.[21] A Phase I trial of this agent in combination with gemcitabine and cisplatin was reported as safe with further Phase II trials warranted.[22] Thus, humanized and human monoclonal antibodies to DR4 and -5 are rapidly being developed with future efficacy trials of these agents in combination with chemotherapy underway

[hutchibk]

I don't understand any of it, Lani... but I will take you at your word that this is exciting!!

[eric]

Same here. Lani, it's rare that I see you this excited. That makes it exciting for me.

Eric

[Chelee]

Joe, If you read this...here is a good example of where we could use someone to interpret/translate article's like this one. If Lani said this is exciting...it has to be!

(So this falls under your thread titled, "New idea's needed") Just an extra reminder and example at the same time.

Chelee

[caya]

I'm with the rest of the group - no capish any of it - but if Lani is excited - me too!!

all the best
caya

[Patb]

Same here, but great
patb

[juanita]

if i understood it i'm sure it would be great news.

[jones7676]

I understood most of it-looked up a few things...hooray! It just might be the "switch" that many people need. I hope the trials are highly successful.
Thanks Lani

[Marily]

Lani,
is the erb2 a subset under her2? I thought erb2 was her2? So I am confused? and how do they test if it is another part of her2 gene? and they are developing meds to go against it.. or meds if herceptin fails you go on this one? (like my building antibodies to herceptin? making a human (not mouse) agent to build in our bodies an antibody to kill the tumor or stop the over expression????
I talked to my Onc. about RANKL but she had not heard about it? I tried to tell her what i thought it ment and she said I was reading too much into this. ?
I believe my friend was just put on mapatumumab she has advanced non-Hodgkin's lymphoma ....the fact that she has not responded to anything and this is working for follicular lymphoma.She does not have follicular lymphoma but her dr called all over US and to European countries and got the information and permission to use it for her with I believe gemcitabine and cisplatin. We are all praying that she will have a positive response to this and not be so ill receiving it. She is not a breast cancer pt but I hope you will all add her to your prayers.
There is so much out there now about breakthroughs since the human genome project was completed it is so exciting.
I would like to here more from you on this and what you understand about RANKL.
PS are you all going to watch on the 18th.. 9-8 central ...lifetime chan. "Keeping hope alive" Dr Slamon says it is not going to follow the book lol but I am certainly not going to miss it. Harry Connick Jr lost his mother to cancer when he was 13.
hugs M

[Belinda]

For being our eyes and ears and diligently going where some of would be totally lost, and bringing us your regular - and wonderful - dispaches from the frontiers of science. This news is exciting, it is amazing to me that it is happenning just 700kms from my home and I heard about it from the other side of the world. Thanks, Lani. Bx

[Chelee]

Ok now...for those of you that understand this...maybe you could be so nice as to shed some light on it with the rest of us that do not understand a word of it?

There are so many of us here that would certainly appreciate it. Come on propeller heads...help us out. Break this down for us and give us some idea of what this is saying?

Chelee

[Chelee]

There must be at least one person that would be so kind as to interpret this for those of us that don't understand it? (Pretty please.)

Anyone up for the challenge? I would certainly appreciate it. Seems quite a few of us our interested in what this article is saying? I'm even more curious now because even Belinda says it's exciting. Come on...someone share this news with us "non-propeller heads".

Chelee

[kk1]

One of the common features of cancer cells is that they don’t die, apoptosis, at rates of normal cells. Cancer cells can be thought of as immortal. For normal non-cancerous cells TRAIL is a cytokine that binds to DR4 and DR5 receptors and forms a complex (ligand) that sends out death signals. In many cancer cells the DR4 and DR5 receptors have point mutations that prevent TRAIL from binding, thus no death signal. Scientists have been working on creating a variants of TRAIL that will bind to these mutated receptors and have hitched it to a monoclonal antibody to deliver it to the cancer cell. These variants of TRAIL bind the cancer DR5 receptor and not healthy cells receptor and result in the cell death complex to form sending out signals to the cancer cell to die. In this study they showed that combining the her2 antibody and and a DR5 antibody with the TRAIL variant resulted in a compete response in mice, while treatment with either agent alone only slowed growth. This is exciting for all types of cancer not just her2 BC.

Lani or others please correct any misstatements I might have made.

[Chelee]

kk1, I almost missed your post. I had given up on anyone replying. I can't tell you how much I appreciate you taking the time to break that down enough so that I understand it. Your a real sweetheart. Thanks a million!

Chelee

[eric]

KK1- what a great explanation. Thank you, Eric