Gone for good.
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There are actually 9 trials underway. The 6 ISTs, the two NSCLCs, and the one pancreatic cancer. All recruiting, or active but not recruiting.
In light of these changes I would not be surprised to see something similar for the pancreatic cancer trial.
The MOS may not be ready for January. Maybe March 2013? Just a guess.
For the first-line NSCLC trial the changes made were:
http://clinicaltrials.gov/archive/NCT01160601/2012_11_29/changes
Estimated Study Completion Date: July 2013 - changed from June 2012
Estimated Primary Completion Date: March 2013 (Final data collection date for primary outcome measure) - changed from April 2012
for both the types remain as "Anticipated". This trial seems to be lasting much longer than first estimated.
Here are the actual changes made. Nothing about MOS or dates of enrollment.
http://clinicaltrials.gov/archive/NCT01138163/2012_11_29/changes
These dates were changed:
Estimated Study Completion Date: March 2013 - changed from June 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure) - changed from April 2012
The interesting part is on line 6 of the changes for the primary completion date:
type="Anticipated" changed to type="Actual"
The type for "Estimated Study Completion Date" is still "Anticipated" and the code lists this as <last_follow_up_date>
I like this. I am going to buy some more.
Exactly. Why would they create a hoax and then expose it themselves? Well, enough time wasted on that.
Thanks to all of you who encouraged me to apply for the medical writer position at Peregrine. I appreciate your kind words.
However, while I would like the writing about the science and preparing posters etc, the part about preparing documents
for the FDA does not sound like fun. For now I will stay here in Denver in the lab.
FTM
To me that implies that Peregrine committed fraud. AF is a real asshole.
I nominate him for Worst Biotech Columnist of the Decade.
The doubling of survival attributed to bavituximab turned out to be a hoax.
I like the sound of that
Your expertise is essential for building clinical reports, investigator brochures, summary of safety and efficacy documents, and other documents that may be submitted to the Food and Drug Administration or other organizations for publication and/or presentation as we prepare to revolutionize patient therapies for brain, lung and pancreatic cancer.
RRdog, yes, I would definitely agree with you on that.
FTM
The March 2013 date is still an estimate, so my guess it could be anytime between now and then. How about this scenario:
Peregrine announces that the second-line NSCLC trial data has been fixed up and the trial continues in the
"active, not recruiting" phase with patients continuing to survive for a few more months until 80% of them have died and
the trial is declared completed. Just a thought.
It is great to see that. I think this means that the MOS for both first-line and second-line NSCLC will be
double that of the control arms. Maybe pancreatic will follow.
Thanks. To me the beauty of the MOA is how it unleashes the immune system to do what it does naturally.
At its root it is also very simple and should work universally. There will probably be ways found to make it
work even better and the imaging tools should prove to be very useful for that purpose.
Yes, there was, but it is not a problem. In fact someone asked Thorpe this question
at the NYAS talk. If I remember he said there is only about 1-2% of the population which
carries a mutation that causes low levels of beta2-GPI in their blood.
I recall in some papers the testing of dimerized beta2-GPI. It does bind to PS, but
then it doesn't have the Fc end of the antibody and so macrophages, DCs can not bind to it.
When experiments are done with bavi in mice human beta2-GPI is also injected because
bavi binds to the second domain of human beta2-GPI, and not to the first domain which is
conserved across many species. I posted this once.
Yes, MFG-E8 is another bridging protein. It binds to PS on apoptotic cells on one end,
and on the other end to macrophages via the alpha V, beta3 integrins. Bavi can not bind to
MFG-E8 since it's specificity is for the second domain of beta2-GPI.
Yes, I was going to point that out.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=75520883
PGN632 binds directly to PS without any need for beta2-GPI.
I just posted that bavi does not bind to PS, but to the second domain of beta2-GPI,
which then binds to PS through the fifth domain. See the figure and paper.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81935248
I can not believe you have not read the fact that bavi (2aG4, 3G4) binds to beta2-GPI. This has been known
since 2006 when this paper was published by Thorpe's lab.
http://www.ncbi.nlm.nih.gov/pubmed/16905548
Plasma protein beta-2-glycoprotein 1 mediates interaction between the anti-tumor monoclonal antibody
3G4 and anionic phospholipids on endothelial cells.
Luster TA, He J, Huang X, Maiti SN, Schroit AJ, de Groot PG, Thorpe PE.
Journal of Biological Chemistry, 2006 Oct 6;281(40):29863-71.
I even posted this picture recently
That is why I said "conveniently" because you seemed to be ignoring facts that did not fit your theory.
The whole notion that bavi is not an antibody is the same thing. The idea that there is a vaccine-like
effect is not new. My post from yesterday shows how it can be used to make a vaccine.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81917943
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81918470
In addition, the existence of long-term survivors in the second-line NSCLC would be strong evidence that
those patients have developed immunity to metastasis of the disaease. The MOA as it is now understood has an
explanation for that and doesn't really require anything else. Thorpe says this in his talks as reactivating the
innate and adaptive immunity. By blocking the immunosuppression the adaptive arm of the immune system is
then allowed to function normally, which results in the generation of antigen-specific CD8 T cells and antigen-specific
B cells and memory T and B cells, which give rise to immunity. Yes, the MOA is a hypothesis and has been, and will be,
revised as new facts become known, but any new version of the MOA has to still explain the current facts.
Thorpe has mentioned several times this study of glioblastoma in rats and how the surviving rats were shown to have immunity.
http://www.ncbi.nlm.nih.gov/pubmed/19887482
He even specifically mentions it in his NYAS talk and shows the survival curve.
He has also talked about the study of prostate cancer in the mouse model and how those 38% survived.
The poster from this year's AACR meeting
Cure of castration-resistant prostate cancer in TRAMP mice by reactivating tumor immunity
with a phosphatidylserine-targeting antibody
Yi Yin, Xianming Huang, Gustavo Barbero, Dan Ye, Philip E. Thorpe
http://www.peregrineinc.com/images/stories/pdfs/aacr_2012_prostate_cure.pdf
I just don't feel that entirely new ideas are needed here. The MOA will be added to and revised, but the MOA as is,
is actually quite radical when you view it in the context of the past. That is all I have to say about it.
Andy, testing my memory, or yours? I believe they did say that there would be data from
some of the ISTs, but like everything else it may be delayed until 2013. The liver trial
might be very interesting. I don't know what the MOS would be for the pancreatic and first-line
NSCLC trials now, but getting longer. I want it to take as long as it wants.
Make that 9 trials now. The prostate cancer IST trial, which was suspended while
it was transferred from UC Irvine to Medical University of South Carolina, is now back
on the ClinicalTrials webpage and recruiting patients again. The PI, Michael Lilly, MD
was recruited by MUSC from UC Irvine.
Ph Ib/IIa Study of Cabazitaxel Plus Bavituximab in Castration-resistant Prostate Cancer
This study is currently recruiting participants.
Verified November 2012 by Medical University of South Carolina
Sponsor:
Medical University of South Carolina
Collaborator:
Peregrine Pharmaceuticals
Information provided by (Responsible Party):
Michael Lilly, Medical University of South Carolina
ClinicalTrials.gov Identifier:
NCT01335204
First received: April 11, 2011
Last updated: November 27, 2012
Last verified: November 2012
History of Changes
Here is figure 4 from that paper.I always thought it was pretty amazing.
Fig. 4. Inhibition of spontaneous lung metastases by 2aG4-IL2/4T1 vaccination. Mice were vaccinated and challenged as described above. On day 35 after tumor cell implantation,
mice were sacrificed and lungs were harvested and fixed in Bouin’s buffer. Metastases on the surface of lungs were counted with the aid of a dissecting microscope. (A) Gross
appearance of lungs from representative mice from each group. (B) Enumeration of lung metastatic nodules. Each data point represents the value for an individual animal
and the line represents the average number of tumor nodules from 10 animals in each group. The numbers in parentheses are the number of mice in each group that had
tumor colonies on the surface of their lungs. There were significantly fewer lung metastatic colonies in the lungs vaccinated with 2aG4-IL2/4T1 (2aG4-IL2 vs 2aG4, P < 0.02;
2aG4-IL2 vs C44-IL2 or C44, P < 0.001). There were also significantly fewer colonies in mice vaccinated with 4T1 cells coated 2aG4 as compared with C44 or C44-IL2 (P < 0.05).
From the Discussion section.
[snip]
In summary, we have shown that a whole cell vaccine created
by coating irradiated tumor cells with anti-PS-IL2 fusion protein
can generate robust anti-tumor immunity. While this study was in
a prophylactic setting, future studies will address the therapeutic
efficacy of this approach in animals from which the primary tumor
has been removed surgically. This treatment setting could begin to
address whether patients who have residual diseases and who are
at high-risk to develop cancer might benefit from immunization
with their own killed tumor cells coated with anti-PS-IL2 [48,49].
Given the broad action of PS-dependent immunosuppression, and
the fact that all killed whole cell vaccines strongly express PS, the
current approach could be generally applicable. It might also be
applicable in a so-called in situ vaccine setting in which a patient’s
tumor is treated with irradiation or other local therapy and anti-
PS-IL2 then injected into the dead tumor tissue [50,51]. Since most
chemotherapeutic drugs and radiation elicit apoptotic cell death, PS
exposed on dead and dying tumor cells would be expected to abrogate
local immunity; if so, intra-tumoral injection of anti-PS-IL2
might simultaneously overcome the immunosuppressive environment
while adding IL-2 to activate immunity.
None of them.
I believe they are referring to this pre-clinical study from 2011.
Enhancing the potency of a whole-cell breast cancer vaccine in mice with an antibody-IL-2
immunocytokine that targets exposed phosphatidylserine.
Huang X, Ye D, Thorpe PE.
Vaccine 2011 Jun 24;29(29-30):4785-93. Epub 2011 May 8.
http://www.ncbi.nlm.nih.gov/pubmed/21557977
Abstract
Phosphatidylserine (PS), an anionic phospholipid normally restricted to the inner leaflet of the plasma membrane, is immunosuppressive when externalized on the outside of cell membranes. Exposed PS inhibits the maturation and function of dendritic cells (DCs), and induces the production of multiple immunosuppressive mediators. In the present study, we determined whether blocking these effects of PS while simultaneously introducing interleukin-2 (IL-2) could improve the immunogenicity of a whole-cell cancer vaccine. An immunocytokine (2aG4-IL2) was made by genetically linking IL-2 with a PS targeting antibody, 2aG4, that can block the immunosuppressive effects of PS. The 2aG4-IL2/4T1 vaccine was generated by coating the PS exposed on irradiated 4T1 cells with 2aG4-IL2. Tumor growth, spontaneous metastasis, and survival of vaccinated mice challenged with live 4T1 tumor cells were assessed. Eighty percent of mice inoculated with 2aG4-IL2/4T1 vaccine survived free of tumor, as compared with 20% in the 2aG4/4T1 group, 20% in the C44-IL2/4T1 group, and none in the C44/4T1 control group (P=0.001 for 2aG4-IL2/4T1 versus all others groups). The incidence, number of spontaneous lung metastases was significantly lower in the 2aG4-IL2/4T1 vaccinated group than in the other groups. Splenocytes from 2aG4-IL2/4T1 vaccinated mice had significantly higher 4T1 specific cytotoxicity and ability to secrete interferon-gamma (IFN?) than did splenocytes from mice in the other groups. These results demonstrate that a potent whole-cell vaccine can be created by coating irradiated tumor cells with 2aG4-IL2. Such vaccine could potentially be an effective treatment modality for patients with residual disease or at "high-risk" for recurrence.
That works for me.
We went over this all recently. There is nothing new here. This was all written last summer.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=81478995
For all you cancer detectives out there I have put together a list of freely available (open access)
journals dealing with cancer and related subjects.
------------------------------------------------------------------
BMC Biology
http://www.biomedcentral.com/bmcbiol
BMC Cancer
http://www.biomedcentral.com/bmccancer/
BMC Immunology
http://www.biomedcentral.com/bmcimmunol/
BMC Medicine
http://www.biomedcentral.com/bmcmed/
Cancer Immunity
http://cancerimmunity.org/
Cancer Medicine (brand new)
http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2045-7634
EBMO Molecular Medicine
http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1757-4684
Frontiers in Immunology
http://www.frontiersin.org/Immunology
Frontiers in Oncology
http://www.frontiersin.org/Oncology
The Journal of Biological Chemistry
http://www.jbc.org/
Journal for Immunotherapy of Cancer (just started by SITC)
http://www.immunotherapyofcancer.org/
Journal of Translational Medicine
http://www.translational-medicine.com/
MicrobiologyOpen
http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2045-8827
Neoplasia
http://www.neoplasia.org/index.php
OncoImmunology
http://www.landesbioscience.com/journals/oncoimmunology/
PLOS Biology
http://www.plosbiology.org/home.action
PLOS Genetics
http://www.plosgenetics.org/home.action
PLOS Medicine
http://www.plosmedicine.org/home.action
PLOS Neglected Tropical Diseases
http://www.plosntds.org/home.action
PLOS One
http://www.plosone.org/home.action
PLOS Pathogens
http://www.plospathogens.org/home.action
Radiation Oncology
http://www.ro-journal.com/
Translational Oncology
http://www.translationaloncology.org/
There is a meeting in January that could be a venue in which to report on either the pancreas or
liver trials. I don't see anything yet, and the possibility of late-breaking abstracts still remains.
2013 Gastrointestinal Cancers Symposium
JANUARY 24-26, 2013
Moscone West Building, San Francisco, California
The Gastrointestinal Cancers Symposium showcases important
advances in research and emerging therapies for GI cancers.
A discussion-based meeting, the Symposium is intended
to foster dialogue among oncologists, surgeons, radiation
oncologists, gastroenterologists, and other members of the
cancer care community. High-impact educational sessions
feature presentations on the latest science and its applicability
to optimizing the treatment of patients with GI cancers.
http://www.gicasym.org/meeting-program
Friday Jan 25th is the day for pancreas and liver talks.
Another meeting sponsored by ASCO and ASTRO
The difference is that one was a post on an anonymous internet board and the other was stated
to the public by a supposed professional analyst as a fact.
While I agree that the stock is purely speculative at this point, I take issue with his
stating that the mix-up involved not knowing who got bavi and who got placebo. If that
is true the information has not been made public, and so amounts to stating untruths.
Check out Brenton Flynn's background. CFA, BS in business, was a professional golfer two years ago.
Not exactly the background I want to see in someone claiming to be a biotech analyst. Nothing
about any past experience in biotech. Has been Healthcare Bureau chief at MF since last month.
http://www.linkedin.com/pub/brenton-flynn/42/34/177
Thorpe's talk is about the MOA and pre-clinical stuff. No reason that would be cancelled. Shan could still
give an overview of all the trials while excluding the second-line NSCLC trial.
Does that mean some of those ambulance chasers are gone if they didn't find lead plaintiffs? Thanks for your opinions.
Thanks. I thought they were DOA too, but wondered if no lead plaintiff was appointed by today if that
means the lawsuits are voided.
What does that have to do with the class action lawsuits?
Could this have anything to do with the fact that today is the deadline for the class action lawsuits? Bungler?
Entdoc, I see these retrospective studies to be supporting of the MOA Thorpe has put forth for the switching
of M2-type macrophages to M1-type, and that this could be a possible explanation for the increased survival
seen in the NSCLC and possibly pancreatic cancer trials. I expect this would apply to breast and prostate cancers also.
Here is a paper which has similar results but in NSCLC. Again a retrospective look at patient samples from surgery.
Here I take "tumor islets" as being the tumor tissue, and tumor stoma as the surrounding tissues.
The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time
BMC Cancer 2010
FREE: http://www.biomedcentral.com/content/pdf/1471-2407-10-112.pdf
------------------------------------------------------------------------------------------------------------
Abstract
Background: Tumor-associated macrophages (TAMs) play an important role in growth, progression and metastasis
of tumors. In non-small cell lung cancer (NSCLC), TAMs’ anti-tumor or pro-tumor role is not determined.
Macrophages are polarized into M1 (with anti-tumor function) and M2 (with pro-tumor function) forms. This study
was conducted to determine whether the M1 and M2 macrophage densities in NSCLC are associated with
patient’s survival time.
Methods: Fifty patients with an average of 1-year survival (short survival group) and 50 patients with an average of
5-year survival (long survival group) were included in this retrospective study. Paraffin-embedded NSCLC specimens
and their clinicopathological data including up to 8-year follow-up information were used. Immunohistochemical
double-staining of CD68/HLA-DR (markers for M1 macrophages) and CD68/CD163 (markers for M2 macrophages)
was performed and evaluated in a blinded fashion. The M1 and M2 macrophage densities in the tumor islets,
stroma, or islets and stroma were determined using computer-aided microscopy. Correlation of the macrophage
densities and patient’s survival time was analyzed using the Statistical Package for the Social Sciences.
Results: Approximately 70% of TAMs were M2 macrophages and the remaining 30% were M1 macrophages in
NSCLC. The M2 macrophage densities (approximately 78 to 113 per mm2) in the tumor islets, stroma, or islets and
stroma were not significantly different between the long survival and short survival groups. The M1 macrophage
densities in the tumor islets (approximately 70/mm2) and stroma (approximately 34/mm2) of the long survival
group were significantly higher than the M1 macrophage densities in the tumor islets (approximately 7/mm2) and
stroma (13/mm2) of the short survival group (P < 0.001 and P < 0.05, respectively). The M2 macrophage densities
were not associated with patient’s survival time. The M1 macrophage densities in the tumor islets, stroma, or islets
and stroma were positively associated with patient’s survival time in a univariate analysis (P < 0.01 or 0.001). In a
multivariate Cox proportional hazards analysis, the M1 macrophage density in the tumor islets was an independent
predictor of patient’s survival time.
Conclusions: The M1 macrophage density in the tumor islets is an independent predictor of survival time in
NSCLC patients.
------------------------------------------------------------------------------------------------------------
Here are the survival curves for the different categories. Survival was much better if there was a higher than median number of
M1 macrophages in the tumors.
Mojojojo,
I'll send them to you. The "high" and "low" refer to the amount of the receptor proteins CD163 and CD204
that were detected on the surface of the tumor samples. A high amount of either of those two proteins is associated
with the M2-type macrophage. In both of these two studies the patients had mostly earlier stage pancreatic cancer
that was removed by surgery and tumor tissue samples stored for later. It was thought that the surgery might
cure them, but the survival curves show the cancer came back over time except for about 20-30% who had survived for 5 years.
So this is a retrospective look at the patients and an attempt to understand what factors were present that
distinguished long-term survivors from those who were not.
The details are that CD204 (SR-A) is a class A scavenger receptor, and CD163 (MR) is a mannose receptor.
There are at least two things wrong with your "theory". Perhaps you remember this picture I once posted.
It shows how an antibody (in the picture the Ab is bound to a molecule) and the receptor may be internalized.
This is called receptor-mediated endocytosis. The receptor may be recycled and be returned to the cell surface,
but the ligand is destroyed inside the cell in a lysosome which has a very acidic environment. The picture is
somewhat simplified here.
So the antibody will not be sticking to the PS on the inside of the plasma membrane.
http://en.wikipedia.org/wiki/Endocytosis
The other big problem is that you seem to conveniently forget that bavituximab does not bind to PS.
It binds to the serum protein beta2-glycoprotein I. That is a protein which circulates in the blood stream,
it isn't present in the cell for bavituximab to bind to.
http://en.wikipedia.org/wiki/Beta-2_glycoprotein_I
Here is a reference you might want to look at. Molecular Cell Biology , by Lodish et al.
There is a section on receptor-mediated endocytosis.
You just can't make up ideas that are contrary to facts without some kind of evidence.
This is the last time I will post on this.