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"The Burrill Mid-Cap Biotech Index continued where it left off in 2006, rising 4% in Q1 07. Most of the jump was recorded in March thanks to Dendreon which soared 179% in March, 210% for the quarter after the FDA recommended approval for its prostate cancer vaccine, Provenge. Studies found that Provenge did not slow progress of the disease, but it could extend patients' lives by 4.5 months by stimulating their immune systems to fight the disease. A final FDA decision on Provenge, also called sipuleucel-T, is expected May."
http://www.genengnews.com/news/bnitem.aspx?name=15150739
"G. Steven Burrill has been involved in the growth and prosperity of the biotechnology industry for over 40 years. An early pioneer, Mr. Burrill is one of the original architects of the industry and one of its most avid and sustained developers. He currently serves as Chairman of the Boards of Pharmasset, and is a member of the Boards of Directors of Catalyst Biosciences, DepoMed (Amex: DMI), Targacept (NASDAQ: TRGT), Proventys and Phytomedics. Prior to founding Burrill & Company in 1994, he spent 28 years with Ernst & Young, directing and coordinating the firm's services to clients in the biotechnology/life sciences/high technology/manufacturing industries worldwide. In 2002, Mr. Burrill was recognized as the biotech investment visionary by the prestigious Scientific American magazine (The Scientific American 50). Mr. Burrill is a founder of the Foundation for the National Medals of Science and Technology and currently serves on its Board of Directors. Some of his not for profit activities include serving on the Boards of Directors for the Bay Area Science Infrastructure Consortium, BayBio, the California Healthcare Institute, the Exploratorium, The Kellogg Center for Biotechnology, Research!America, Campaign for Medical Research, The National Health Museum, and the University of California, San Francisco (UCSF) Foundation. He is also the Chairman of the Mayor’s Biotech Advisory Committee (MAYBAC)."
http://www.burrillandco.com/bio/team_bios
"In 1994, G. Steven Burrill founded Burrill & Company as a logical extension of his 35+ year involvement in the growth and prosperity of the biotechnology industry. Mr. Burrill has been an active advisor and catalyst in some of the industry's most notable companies and transactions. Mr. Burrill's close involvement and respected position within the industry has positioned the firm as a prominent deal-maker and facilitator of industry partnerships and alliances, all of which fosters a robust deal flow. Further contributing to this deal flow are: the scientific and business networks of its investment team; the Advisory Boards; the strategic and financial network of its limited partners; and the close relationships developed with numerous life science companies and management as a result of Burrill's visibility, reputation, and the firm's partnering and alliance work.
Having created a strong organization of respected professionals from the life science industry worldwide, Burrill & Company stands in the mainstream of life science deal flow and its visibility in the industry is unrivaled."
http://www.burrillandco.com/burrill/history
sounds like these guys know a good speculative biotech when they see one. i wonder too, whether they may have gotten an inkling about a possible partnership deal at the JP Morgan (aka H&Q) healthcare conference in San Fran back in Jan/07?
here is a link to an earlier article from the same source...
Late-Stage Cancer Vaccines Set to Launch With Five Major Players
Therapeutic Vaccines Could Transform Medical Care
Rod Raynovich
"Over the past few years, there has been a surge of interest in vaccines. Market growth rates are forecasted at 20% per year over the next five years with the introduction of HPV, influenza, rotavirus, shingles, and meningitis products. R&D investment is growing with the NIH funding a number of bioterrorism projects and the Bill and Melinda Gates Foundation backing a range of vaccines. The worldwide prophylactic vaccine market is expected to reach $15 billion in 2010, up from $10 billion in 2005.
Active immunotherapy, however, has proven to be a difficult development area, with a significant number of clinical failures, primarily for melanoma and pancreatic cancers. But, 2007 could be a pivotal year, bringing new technologies and positive clinical developments for therapeutic cancer vaccine products.
New technologies include DNA and cellular delivery, TLR receptor agonists, and adjuvants. A recent report published by Kalorama Information, “The Emerging Cancer Vaccine Market”, (see BioMarket Trends in the January 15, 2007, issue of GEN) forecasts a $700-million market by 2008 and $8.4 billion by 2012, initially driven by Merck’s (www.merck.com) Gardisil. Highlighted here are five well-funded public companies with proprietary technology and late-stage trials utilizing active immunotherapy along with combination therapy to complement antibody treatment and chemotherapy.
Dendreon’s (www.dendreon.com) method is to use a selected cancer–related target protein to stimulate a patient’s own dendritic cells, which are then reinfused into the patient to stimulate an immune response.
The company’s primary candidate, Provenge (sipuleucel-T), is an active cellular immunotherapy for the treatment of metastatic androgen-independent prostate cancer. It recently completed Phase III trials. The FDA assigned priority review status to the company’s BLA, which is expected by May 15, 2007, but may be as early as March 29. The BLA submission is based primarily on an improvement in overall survival, reported in the July issue of the Journal of Clinical Oncology.
Dendreon also completed a Phase I evaluation of Neuvenge, an investigative active cellular immunotherapy for the treatment of breast, ovarian, and colon cancers. Phase II should be initiated in 2007.
It has collaborative agreements with Genentech (www.gene.com) for the development of products derived from trp-p8, an ion channel found in prostate cancer cells, and Abgenix/Amgen (www.amgen.com) for the development of Mabs against membrane-bound serine protease, which is implicated in solid tumors.
JMP Securities and Needham have a buy rating on the stock."
http://www.genengnews.com/articles/chitem.aspx?aid=2019
wall, that is not accurate.
$53.2M leftover from the previous shelf must be common, but the remaing $147 could be any combination of preferred, debt, warrants including commmon.
http://google.brand.edgar-online.com/fetchFilingFrameset.aspx?FilingID=5040858&Type=HTML
fwiw, i expect they will issue common for most if not all of the $147M since i expect a chunk of that will go to a partner in the form of an equity investment, plus the company has forecasted that they will be cash flow negative for the next two years (additional Provenge trials, Neuvenge, trp-8, re-starting R&D, etc.), making interest or preferred dividend payments on issuance of debt/preferred equity less attractive, plus i suspect they are thinking that dilution via common will be less of an issue as the price increases.
the one fly in the ointment is the artifical depression of the market price due to naked short selling which directly impacts the equity interest of every existing long...that is something the company, in particular Schiffman should be addressing whether with the SEC, and/or via alternative means, such as issuing a property dividend of stock warrants to shareholders of record or similar action.
fwiw, i have given up reading most of the IV MB posts, in part because the one aspect where the leverage of apparently 11M DNDN shares held by IV MB readers could, imo, be effectively applied has been essentially ignored by that MB, in favor of pursuing hussain or some other negative panel members. if you really want to screw the shorts, that is the best and perhaps only way to actually do so.
i thought they would raise cash before the panel, since a negative recommendation could have been potentially disastrous, especially considering the heavy manipulation the stock has endured (and continues to after the favorable panel decision, imo).
as a long, i wouldn't have had a problem with a pre-panel financing, or if they decide to do one before approval.
based on the post-panel price and the $147M mixed shelf, dilution would represent approx 10 to 15% and given the near term prospects for some ROW partner cash & early indications (3rd qtr) of the rate of uptake for Provenge in the market, i think the market will start to price in higher sales multiples if the numbers reflect positive trends, which should help minimize future dilution.
then consider the value of their immunotherapy platform for other cancer indications, and dilution is not that big a concern...execution of their sales/market penetration is/will be more important.
jmo
Thank you Wall for sharing your expertise and experience.
to a layperson like myself, it is a bit unnerving to see how these reviews are conducted and ultimately decided...compared to the apparent level of rigor that the trial results and stats analysis are subjected to before it gets to the public testimony stage.
thank God for Dr. Mule asking that the FDA clarify the efficacy question and ultimately for the CTGT & not ODAC holding the AC meeting.
just a guess, but it seems to me if this panel had been convened by pazdur & ODAC, it might have been a different outcome.
In any case, congratulations & many thanks.
Congratulations to AIPC patients, DNDN management, and all DNDN longs, especially those posters on these MBs who contributed to an objective understanding of the science risks to laypeople like myself. (You know who you are.)
Tomorrow should indeed be an interesting day - the long night's journey for DNDN shareholders has passed into the dawn of a new era in cancer treatment, with the light beginning to shine brightly on Provenge as it basks in the glow of FDA approval.
Cheers.
I don't think anyone who has been following DNDN closely the past couple of years would deny that there has been blatant stock manipulation going on by large institutional hedge funds & shorts (long before it recently made the Reg SHO list), but aside from a few of the most knowledgeable and reasoned posters, i have to agree with the observation that the IV board has been overrun with "retail" emotion, probably due to the very manipulation perpetrated by the shorts & hedge funds and their flunky analyst co-conspirators over the past couple of years.
such susceptibilty for small, vulnerable investors to want to exact revenge after enduring such a long period of manipulation and abuse is perhaps somewhat understandable and may satisfy a person's lower nature & desires, but imo, it does not represent a healthy platform from which to make investment or for that matter, even trading decisions (imo, such overly emotional thinking feeds right into the shorts/hedges strategy, whether intentional or otherwise). I think such emotion is better saved for and served on the SEC and yes, even the company as to what they are going to do about this problem that directly impacts small, vulnerable shareholders. (and yes, i have written the SEC and an independent director of Dendreon asking what they are going to do about the naked shorting of DNDN shares).
as a layperson, I am hopeful of a positive panel recommendation tomorrow, in large part due to the encouraging feedback to the briefing docs, from people like yourself, clark, io, ocyan & wall, etc., who have been thru this process before and who have been very grounded in their views and outlook for Provenge & the AC panel.
i am also hopeful of a multi-bagger with DNDN, but understand it may take months if not years to realize that potential, particularly with an apparent powerful adversary in the form of short/hedge funds - if the stock gets carried away and the multi-bagger happens much sooner than that, all the better, but i am prepared & expect to wait it out to realize that goal - i certainly don't want to contribute to creating expectations that are overly optimistic or unrealistic based on an appeal to emotion, and try to keep a healthy respect for market forces, particularly when some of them are corrupt to the core while seemingly operating freely with impunity.
to underestimate or disregard an enemy as powerful as they have been allowed to demonstrate, with the complicity of the brokerages, exchanges and regulatory authorities would be extremely foolish, imo.
best of luck to real(istic) DNDN longs and may PC patients triumph over process tomorrow.
Petrylak's complete Nov/06 presentation on Sipuleucel-T followed by Taxotere is now online.
go to the following link, scroll down about half way down the page under GU Cancers - & click on the View Presentation
http://chemotherapyfoundation.org/professional_education/meetingarchives_tcf2006_main.html
The BLA is based on stats sig OS in 01, with other supporting data (mainly OS in 02B and TTP in 01
i know the question of 9901's TTP "near miss" has already been hashed out quite a bit, including the lowering from .06 to "virtual" significance of .052 on final publication of the results (i don't recall the exact numbers offhand), despite the increased amount of time the immune system needs to ramp up after the vaccine, and the apparent detrimental method in how TTP was measured per 9901 (due to differences in when the clock started to measure ttp, if i understand correctly.)
best i can understand, TTP was largely discredited as a valid endpoint for PC, as concluded at an NCI or FDA sponsored PC workshop a year or two ago, IIRC. Consequently, it has been postulated (imo correctly) that Dendreon won't be relying on their near miss in TTP in 9901 to make any of their case in front of the panel.
as a layperson, i wonder whether DNDN's near TTP miss in 9901 may cause the usefulness of this endpoint for PC to be revisited? while DNDN may not use 9901 TTP results to support the case for Provenge approval, wouldn't the panel members aware of the problems of coming up with meaningful surrogate endpoints for PC survival look at the 9901 TTP result in a positive way, perhaps even supportive of approval?
just thinking out loud & on paper...
interesting find.
certainly seems like these individuals will form at least part of the committee members, IF the Director of The Division of Scientific Consultants & Advisors' request for a waiver in relation to prohibition against their declared conflict of interest is granted.
the following appear to be members of CDER that have been conditionally selected to be part of the advisory committee.
it appears that there may be others not listed here who have no declared conflict of interests, but may still form part of the apparent hybrid committee.
Maha Hussain, M.D., a special Government employee for the Center for Drug Evaluation and Research. Dr. Hussain was invited to participate as a consultant at the Cellular, Tissue arid Gene Therapies Advisory Committee meeting on March 29, 2007.
Dr. Hussain advised the FDA that she has a financial interest related to the above topic that could potentially be affected by her participation in the matter at issue. Dr. Hussain reported that her husband owns stock in the following competing firms:XXXX,XXXX,XXXX,XXXX. Dr. Hussain does not hold control in the purchase or sale of the stocks. Dr. Hussain also is the principal investigator on an unrelated research contract awarded by a competing firm. Dr. Hussain's institution receives approximately XXXX per year fiom May 2006 to September 2009. She does not receive any personal remuneration. This research contract does not entail a direct and predictable affect on the interest.
Derek Raghavan, M.D., Ph.D., a special Government employee for the Center for Drug Evaluation and Research.
Dr. Raghavan advised the FDA that he has a financial interest related to the above topic that could potentially be affected by his participation in the matter at issue. Dr. Raghavan reported that he has a grant from XXXX. The grant is current and awarded to his institution. His institution receives XXXX from 2006-2007. Dr. Raghavan receives no direct support from the grant. The grant is to study a licensed, approved drug XXXX in prostate cancer trials.
Howard I. Scher, M.D., a special Government employee for the Center for Drug Evaluation and Research. Dr. Scher was invited to participate as a consultant at the Cellular, Tissue and Gene Therapies Advisory Committee meeting on March 29,2007.
Dr. Scher advised the FDA that he has a financial interest related to the above topic that could potentially be affected by his participation in the matter at issue. Dr. Scher reported that he has joint stock in XXXX a current value of XXXX. Additionally he reported that his institution has a grant from XXXX(competing firm). The grant is current and his institution receives XXXX per year from 2006-2007. Dr. Scher receives no salary from the grant. The grant is to study a licensed, approved drug XXXX in prostate cancer trials.
DNDN hasn't enough cash to make a product to sell unless they merge with a cash-rich partner -- FDA approval means little to a dirt-poor outfit like this -- IMHO --
i agree that DNDN needs to find cash soon, whether from a partner or financing, but disagree that FDA approval means little.
while the shorts/hedges have successfully managed to cap the share price for well over 2 years since 9901 final results were released indicating statistically significant 3 year survival numbers across all gleason scores, FDA approval should provide some relief to the company in the form of a higher share price (driven by a combination of short covering & institutional buyers currently sitting on the sidelines).
FDA approval is also expected to bring a ROW partnership agreement which may also involve cash infusion perhaps with an equity stake, but i don't expect a "merger" you refer to or "lowball" buyout if Provenge is approved.
Management has retained total control of the drug and forgone partnering while diluting shareholders at a discount twice so far in the past 2+ years, so i don't expect they will suddenly change their minds and "sell out" shortly after approval before giving themselves an opportunity to see how far they can take Provenge & the rest of their pipeline. jmo
Interview with Dr. Petrylak re: his Sipuleucel-T Chemo Symposium presentation (first 4 minutes of the file)
http://www.asco.org/pc/mediafiles/ajoia/2006/11/0611151stASCOpodcast.mp3
from his responses, it seems to me he is already looking ahead to pre-clinical models to design combo studies to figure out the best way to integrate/sequence Provenge & docetaxel treatments in order to obtain the optimal interaction between the two, essentially assuming approval, until the interviewer asks whether the "provocative" data needs to be looked at prospectively - i.e., Sipuleucel-T needs to be approved first, where the good Doctor seems to catch himself, and acknowledges it needs FDA approval first before looking at "a lot of work to do in the future"
MediGene and Sanofi Pasteur Agree to Undertake a Collaborative Research Agreement to Develop High Affinity Monoclonal T cell receptors (mTCRs) for Vaccine Validation
Dec 19, 2006 | MediGene AG, (Frankfurt, PrimeStandard: MDG) announced today that it has signed an agreement with sanofi pasteur, the vaccines business of sanofi-aventis. The agreement is to use the novel high affinity monoclonal T cell receptors (mTCRs) to directly validate presentation of specific T cell epitopes important in vaccine development and clinical trials. MediGene recently acquired the mTCR technology with the acquisition of Avidex Ltd.
The highly innovative mTCR technology enables the production of fully human, soluble T cell receptors with high affinity. These mTCRs recognise and bind to specific antigens presented by the Major Histocompatibility Complex (MHC).
MediGene will undertake the research programme using high affinity mTCRs which recognise specific HLA-peptide complexes on the surface of antigen presenting cells or tumor cells. The research has the objective of creating vaccine validation tools for sanofi pasteur by detecting these complexes.
"Currently we are developing mTCRs as therapeutics. However, here we will use mTCRs to validate the presence of certain epitopes relevant to sanofi pasteur's vaccine portfolio" said Dr Peter Heinrich, CEO of MediGene. "Today's announcement highlights the versatility of our mTCR platform and our ability to create early value from our mTCR platform through partnerships" he added.
About mTCRs: The breakthrough monoclonal T cell receptor (mTCR) technology platform enables the production of fully human, soluble T cell receptors with picomolar affinity and exceptional selectivity. Unlike conventional therapeutic antibodies, mTCRs are ideal for targeting agents for all disease proteins; including intracellular tumour targets thereby offering a substantial advantage in the number of disease specific targets available. Avidex has assembled a toolbox of fusion partner effector molecules for targeted delivery by mTCRs to allow the rapid development of therapeutic products against a range of disease types. mTCRs have also been used to successfully validate the presence of cancer antigen targets for therapeutic vaccine use, offering significant advantages both during vaccine development and subsequent batch QC.
http://www.pipelinereview.com/joomla/content/view/8765/117/
any comments from our resident science people? - i believe medigene is working with potentially oncolytic viruses though this seems potentially related to cancer vaccines, but have to admit it is over my head...
Dew
I don't disagree that there are a lot of DNDN shareholders who are emotionally & perhaps financially overinvested in the stock, however, by comparing DNDN to the NFLD board, do you mean to suggest that DNDN will not so much as even get an approvable letter from the FDA?
you make reference to the outcome of the 9902B trial, implying that those results will be as disappointing as today's NFLD announcement (and thus lead to complete failure).
do you have any basis in fact for making such implications?
Anyone have a spare $2,750?
To date, no active specific immunotherapies (specifically targeted to a type of cancer) have been approved by the FDA. The most advanced example is Dendreon’s Provenge. Dendreon is submitting a rolling BLA (Biologics License Application) to the FDA for Provenge, for treatment of advanced hormone-refractory prostate cancer. Clinical trial data supporting this BLA, and available data on other cancer immunotherapies and vaccine, are discussed in the report. The report also includes interviews with experts in the field of cancer immunotherapies and vaccines, who discuss the progress, and the challenges and hurdles,faced by researchers and companies working in this emerging field.
http://www.advancesreports.com/ExecSum/CancerIM%20Exec%20Sum.pdf
Sanofi actually has an "active" immunotherapy research program, so their interest in this area isn't as surprising as it first seemed.
the following dated article refers to it
"the R&D centres studying cancer immunotherapy of Sanofi-Pasteur and GSK are respectively in Toronto http://www.cancervaccines.com/?fa=home/about Brussels http://www.gskbio.com/webapp/CM/CM_Entreprise.jsp"
the article goes on to discuss 3 domains of immuno-therapeutics namely Adoptive Immunotherapy,Non-antigen-specific Active Immunotherapy and Antigen-specific Active Immunotherapy (vaccines) & their status to date.
interestingly, under the heading "What is the future..." it has this to say...
"Immunotherapy cancer strategies will occupy a growing part of the therapeutic cancer arsenal. In the short term sales will increase specifically through the impetus of monoclonal antibodies. In 2014 three blockbusters will dominate the market with a turnover of over one billion dollars: Rituxan, Herceptine and Avastine. Moreover, recent studies have demonstrated the efficacy of Herceptine in patients with less advanced breast cancers, leaving the way open for broader indications for use of these monoclonal antibodies.
The breakthrough of therapeutic vaccines is much less certain. 2010 sales projections vary by a factor of ten between 600 million and 6 billion dollars. What is sure is the necessity of a primer with the first convincing product accepted. The most promising current candidates are Provenge (Dendreon) and PANVAC-VF (Therion), acting respectively against metastatic cancers of the prostate and the pancreas. Where immunotherapy was envisaged as substitution therapy just a few years ago, combinations with other therapies (notably chemotherapy) are now starting to appear.
http://www.parisdeveloppement.com/la-technopole-parisienne/les-poles-innovants/pole-sante/actualites...
Interestingly, Paris Development appears to be an initiative of both the City of Paris and the Paris Chamber of Commerce and Industry, to promote economic growth in the French capital and appears to have only one biotech industry representative on its BoD...Philippe TCHENG, Public Affairs Director, Sanofi-Aventis.
I think it is way too premature to suggest that Sanofi is interested in owning much less buying DNDN or to make a big splash at a symposium organized by & presumably exclusively for eggheads, but I do think they have to have an interest in potentially partnering and wonder if DNDN's choosing of a late breaking session at ECCO 13 in Paris for Higano's 9902A presentation was more than just coincidental?
The Potent New Anti-Tumor Immunotherapies Symposium Mar 28 to Apr 2, 2007
"For the first time, significant numbers of patients with some solid cancer histologies can be successfully treated using immunological means. Progress in our understanding of immune activation, homeostasis and regulation has reached a “tipping point” that has enabled the development of multiple anti-tumor immune-based strategies. Adoptive cell transfer (ACT) of anti-tumor T cells after the depletion host immune cells causes objective regression in about 50% of the patients. Work on therapeutic cancer vaccines is intensive and will actively be discussed at the meeting. The challenge now is to control and direct the potent new weapons in at the immunotherapist’s disposal. This meeting will bring the key scientists who are securing the basic foundations of the new immunology and the translational immunotherapists who are pioneering strategies that objectively work in the clinic."
It doesn't appear that DNDN is represented, but it does look like some of the heavyweight researchers of this emerging field will be there speaking, including
March 29 - 8 to 9am Steven A. Rosenberg, NIH,
Current Immunotherapies Based on Lymphodepletion and Adoptive Cell Transfer
Mar 29 2:30 to 4:30 pm Ulrich H. Von Andrian, Harvard Medical School, Migratory Properties and Immunological Consequences of Dendritic Cell Migration
Mar 30 8 to 9am Nicholas P. Restifo, NIH. The future of adoptive immunotherapy
Restifo also is listed as the organizer of the symposium.
what is rather interesting is that the sponsor of this Immunotherapy event happens to be Sanofi-Aventis...
http://www.keystonesymposia.org/Meetings/viewMeetings.cfm?MeetingID=846&subTab=program
Earlier use of Prostate Cancer Vaccines urged by Hopkins Scientists
Somewhat dated, but interesting article.
Timing is everything when it comes to killing prostate cancer cells with specially tailored vaccines, say scientists testing the drugs in mice at the Johns Hopkins Kimmel Cancer Center.
"The window of opportunity is narrow for vaccination, designed to reinvigorate the immune system's attack on cancer cells, and it occurs right after hormonal therapy begins to wipe out the tumor and immune cells outnumber cancerous ones," according to Charles Drake, M.D., Ph.D., assistant professor of oncology and director of the research which is published in the March issue of Cancer Cell.
Charles Drake, M.D., Ph.D., assistant professor of oncology
In the Hopkins studies with mice bred to develop prostate cancer, Drake and his collaborators at the University of Connecticut found that the animal's immune system recognizes the cancer but fails to mount an attack, probably because immune cells become tolerant of the slow-growing cancer.
"The mice get used to the cancer very slowly over time," Drake says. "But we found that if we use the vaccine to activate the immune system right after we give the mice hormone therapy to shrink their tumors, T-cells start a reaction against the cancer."
T-cells are responsible for recognizing foreign cells and marking them for destruction. Changes in proteins on the T-cell's surface give clues to whether they "see" the cancer and are targeting it. Those cells that have been ignoring the cancer need time to regroup and multiply in order to mount an attack, the scientists say.
T-cells multiplied three times as much in prostate cancer mouse models that were given vaccinations immediately after hormone therapy as opposed to those not receiving hormone therapy. "It's not immunological magic," Drake notes. "It makes sense that when hormone therapy gets rid of cancer cells and the protein antigens they carry, it's easier to re-educate the immune system to fight cancer cells when they come back in smaller numbers."
"If our findings are confirmed, we believe human vaccines stand a better chance of getting T-cells to respond after most of the tumor is destroyed by hormone therapy," says Drake. "The strategy thereafter would be to continue activating the immune system with repeated vaccines and delay the time until the patient needs more hormone therapy, other treatments or lives old enough to die from other causes."
"Most prostate cancer vaccines currently are tested on men whose cancers are growing and no longer responsive to hormone therapy," says Drake. "Fewer than 20 percent of men respond to vaccines alone." Drugs that suppress male hormones such as testosterone, which fuels prostate cancer, are one of the main treatment alternatives for early relapse and helps stall cancer growth.
No clinical trials are yet available for the earlier vaccine regimen.
Prostate cancer is the leading cause of cancer deaths in American men. The average time to relapse after beginning hormone therapy is approximately two years.
http://www.hopkinsmedicine.org/Press_releases/2005/03_15a_05.html
also from the same researcher, another interesting article from last year
Immunotherapy: Making it Better
The idea of using a man’s own immune system to fight cancer has intrigued scientists for years. It makes perfect sense: The body is supposed to attack harmful invaders, and it does a great job protecting us from most of the germs, viruses, and disease-causing agents we encounter throughout our lives. It even fends off most cancer for decades.
But this idea, called cancer immunotherapy, has not progressed as successfully as scientists had hoped it would. One major hindrance may be a well-meaning but misguided group of cells called regulatory T cells,which shut off the body’s immune response.
Drake and colleagues, using a mouse model of prostate cancer, have been able to isolate regulatory T cells from prostate tumors. His next step will be to characterize these cells, “with the eventual goal of blocking their function so that immunotherapy for prostate cancer will be more successful.”
Earlier experiments have provided some clues about how these regulatory cells work, he adds. “They seem to depend on a substance known as transforming growth factorbeta (TGF-β).” Drake will determine whether blocking TGF-β will help immunotherapy for prostate cancer work more effectively. All of this work, in turn, “should provide new insights into the role of regulatory T cells in prostate cancer, and help us to design combination immunotherapy strategies that will be more successful in treating patients.”
http://urology.jhu.edu/newsletter/prostate_cancer87.php
Interestingly, John Hopkins is also home to Mario Eisenberger, a very skeptical reviewer of Provenge immunotherapy studies...who emphasizes that Provenge didn't delay disease progression while questioning whether it was taxotere or provenge that contributed to the increased survival observed in the trials...he also just happens to be lead investigator of the ATLAS study (Adjuvant Taxotere and Leuprolide Acetate Study)- involving more than 2,000 patients from more than 20 countries world-wide.
It will test whether immediate hormonal therapy using leuprolide acetate (which stops the production of testosterone) with or without taxotere, started right after surgery, works better than treatment with the same drugs given months or years later, when the cancer shows the first sign of recurrence (when the PSA starts climbing).
http://urology.jhu.edu/newsletter/prostate_cancer827.php
Migratory Properties and Immunological Consequences of Dendritic Cell Migration...
Ranchero, I'm sure you came across the article referenced in the article linked below, but thought i would post anyways (the article in JEM requires subscription).
"Using advanced new microscopy techniques in concert with sophisticated transgenic technologies, scientists at The Wistar Institute have for the first time created three-dimensional, time-lapse movies showing immune cells targeting cancer cells in live tumor tissues. In recorded experiments, immune cells called T cells can be seen actively migrating though tissues, making direct contact with tumor cells, and killing them.
Insights from this new view of the body's on-board defenses against cancer may open the way for improved immunotherapies to treat the disease.
"We've taken the first real-time look at the final phase of the immune system's response to cancer cells," says Wolfgang Weninger, M.D., an assistant professor in the Immunology Program at Wistar and senior author on the new study. "This has enabled us to delineate the rules of T cell migration and engagement directly within the intricate microenvironment of tumors."
The scientists used a leading-edge instrument called a two-photon microscope, able to peer inside living tissues. The microscope tracked and recorded the movements in three dimensions over time of T cells in a transgenic mouse developed by Weninger and Ulrich von Andrian at Harvard Medical School in which the cells fluoresce green. In addition, for this study, tumor cells in the mice were engineered to fluoresce blue.
In one group of the mice, a vaccine developed by Wistar professor and study co-author Hildegund C.J. Ertl, M.D., was used to activate the T cells that recognize a molecule on the surface of the tumor cells. Such molecules are referred to by immunologists as antigens. In a second group, no such vaccine was given.
Movies captured with the two-photon microscope then recorded the unfolding scene in the so-called tumor microenvironment. How would the green T cells behave in the two groups of mice?
"In the animals that received the vaccination, we saw two waves of activity after the T cells entered the tumor microenvironment," Weninger says. "Early on, the T cells didn't actively migrate through the tissue. This, we found, was because they were interacting directly with the tumor cells in place. In several instances, we were actually able to see the tumor cells dying - the first time that has ever been observed in real-time in living animals. Then, once the tumor cells had been destroyed, we saw a dramatic change in the behavior of the activated T cells. They began to migrate actively, searching for any other tumor cells that might remain in the area."
In contrast, in the mice that did not receive the vaccination, the T cells were much sparser and, importantly, distinctly inactive in their migration. Consequently, tumor cell death was very rare under these conditions.
The researchers then designed a second set of experiments to complement the first. In the first set of experiments, the T cells were varied in two groups of mice while the target tumor cells were uniform. In the second set, the T cells were uniform while the tumor cells varied in two groups of mice according to whether or not they presented a specific antigen to which the T cells would respond.
T cells were removed from mice without tumors, activated in the test tube, and then reintroduced into mice carrying tumors that either did or did not express the antigen. This procedure, referred to as adoptive transfer, is an immunotherapy strategy against cancer being tested in a number of human clinical trials. In some of those trials, a patient's own T cells are removed, tested for their ability to recognize the patient's cancer cells, activated and expanded greatly in numbers in the laboratory, and then returned to the patient.
The hope in these trials is that these enhanced T cell populations will specifically target and destroy the patient's cancer. To date, despite a few remarkable successes, these trials have proven frustratingly uneven. Greater insights into the mechanisms of interaction between T cells and tumor cells could provide vital new information to advance these efforts.
"Through adoptive transfer," Weninger explains, "we were able to compare two situations, one in which the T cells recognize something on the tumor and one in which they don't. When the T cells recognized the antigen, they interacted directly with the tumor cells. After tumor cell destruction, they became actively migratory, hunting for more tumor cells. In the absence of antigen, the T cells did not interact with tumor cells, and could not sustain an active migratory behavior within tumors."
"There are several significant conclusions from these experiments," Weninger says. "First, it is now possible to visualize the behavior of the individual cellular components of the tumor microenvironment in real-time. Second, we have demonstrated that T cells physically interact with tumor cells, which had not been shown before. Finally, it's the presence of antigen that determines how T cells migrate and interact with the tumor cells.
"These experiments set the basis for unraveling the molecular requirements for T cell migration and T cell-tumor cell interactions. We should then be able to use results from this research to further improve immunotherapeutic strategies against cancer in patients."
Their findings, published online will appear in the November 27 print edition of The Journal of Experimental Medicine.
http://www.medicalnewstoday.com/medicalnews.php?newsid=57202
The jury in Oakland, California, federal court awarded Genentech and Tercica $7.5 million in damages and a percentage of future sales of the treatment.
Genentech and Tercica sought damages of $10 million, receiving $7.5 million as part of today's verdict. The jury also awarded the plaintiffs a 15 percent royalty, or as much as $15 million, on the first $100 million of Iplex sales. Genentech and Tercica also received a 20 percent royalty, or as much as $20 million, on the second $100 million of Iplex sales.
The jury verdict was ``disappointing but not surprising,'' said Henry Bunsow, a lawyer for Insmed. He said he would appeal. Lawyers for Genentech and Tercica asked the court today for an injunction barring future sales of Insmed's treatment.
http://www.bloomberg.com/apps/news?pid=conewsstory&refer=conews&tkr=INSM:US&sid=aECqjSdr...
Thanks very much for your insights Ranchero.
to test my own comprehension, I thought I would try to restate in my own words what i thought you were saying, in addition to my own observations of the slides.
Though median survival for both cumulative CD54 Cell count & Upregulation was about 30 months, the survival rate at 36 months was higher for cumulative CD54 Upregulation than for the cell count. In addition, the differences noted between cumulative CD54 upregulation above & below the median were statistically significant (log rank p=.006) compared to the differences between cumulative CD54 cell dosage above & below the median where log rank p=.237
the greater the CD54 expression & upregulation, the greater the stimulation/proliferation of prostate cancer fighting T cells.
CD54 expression/upregulation represents a measure of the potential potency of Provenge that would be important to measure prior to treating the patient (to ensure adequate potency & resulting success). One of the factors to consider here is the role played by Regulator T cells that appear to significantly inhibit the effectiveness of CD8 effector T-cells from staying attached to & thereby killling the target cancer cells. There are a number of possible approaches to controlling or limiting T Reg cells negative impact on effector cells such as antibodies against CTLA4, PD1, LAG3, or ONTAK. Taxotere's possible preferential destruction of TRegs may also explain its apparent synergy with Provenge.
Dendritic Antigen Presenting Cells (APCs) derived from bone marrow have the unique property of avoiding the thymus and its potentially destructive impact on APCs. In addition bone marrow APCs are a source of long term memory T-cells. This long term memory characteristic could assist in maintaining T-cell proliferation & effectiveness for longer periods thereby potentially providing longer protection against possible recurrence of the cancer cells. The patient's T-cell proliferation data would be monitored regularly and he would be given a booster shot as needed (for example when the CD54 expression/upregulation representing PAP specific antigen presentation activity, falls below a certain pre-defined level).
The use of a Provenge booster shot in P-11 appears to have had a significant effect on T cell proliferation, much greater than that achieved by NCI/Therion phase 2 for PROSTVAC and much longer lasting than that achieved by Dr. Rosenberg's genetically engineered T-cells for use in melanoma, suggestive of DNDN's leadership position with its APC casette technology.
This is suggestive of DNDN's leadership position with its antigen casette technology.
It took me a while to get all this (assuming my understanding is correct)...yet i feel i've only barely scratched the surface.
many thanks Ranchero for your always informative, interesting & provocative posts.
Somatic Cell Therapy Symposium - Sep 2006
http://www.celltherapysociety.org/files/PDF/Somatic_2006-Presentations/RT1-Liu.pdf
Not sure if this has previously been posted - apologies if it has.
looks similar to the slides of Provost's Feb/2006 FDA committee presentation, though perhaps updated, though difficult for this layperson to tell.
the two KM survival curves highlighting the differences in survival between patients whose Cumulative CD54 Cell Dose was above & below the median as well as Cumulative CD54 Up-regulation above vs. below the median are a little more legible in these slides than Provost's presentation.
wish there was a way to rec posts over here like there is on iV, as i'd like to recommend yours.
i guess in a way, i just did...
typo correction
If DNDN can'reliably identify and quantify pure Provenge's benefit from the existing trial data, that might be a contributing factor to why they haven't made a partnership deal yet...
should be "if DNDN can't reliably..."
A bigger question is 'why does it matter'. There are many many drugs out there that have beneficial/negating interactions where no one really understands the nuances of the interactions.
fwiw, in my admittedly layman's view, I can't imagine the FDA will turn down Provenge for the above reason if they otherwise think the results from the trials are significant enough, particularly if they were produced by following the very protocol(s) the FDA themselves originally reviewed & approved.
I think the question (& more importantly the answer(s) to the question) do have relevance to the commercial aspects of Provenge if & when approved. in particular, if the survival benefit of Provenge alone is similar to the benefit of taxotere alone, but both are much smaller compared to the benefit from Provenge followed by taxotere, imo, there could be some significant commercial implications for Provenge & DNDN, not the least of which might be partnership possibilities with Sanofi.
If pure Provenge generates a significantly greater survival benefit on its own than taxotere alone (but still significantly less than Provenge followed by taxotere I would think DNDN would have much more leverage in any partnership negotiation with Sanofi than the case where pure Provenge's survival benefit is not much different than taxotere by itself.
If DNDN can'reliably identify and quantify pure Provenge's benefit from the existing trial data, that might be a contributing factor to why they haven't made a partnership deal yet...
In any case, i have to imagine that Sanofi would be very interested in Provenge given Petrylak's study results and how Provenge might help boost taxotere's apparently disappointing AIPC related sales.
New Data Analysis Presented at Chemotherapy Foundation Symposium
The abstract, entitled "Defining the Optimal Role of Immunotherapy and Chemotherapy: Advanced Prostate Cancer Patients Who Receive Sipuleucel-T (PROVENGE) Followed by Docetaxel Derive Greatest Survival Benefit," was presented today at the Chemotherapy Foundation Symposium in New York by Daniel Petrylak, M.D., associate professor of medicine at the New York-Presbyterian Hospital at the Columbia University Medical Center.
"The results of this analysis suggest that the use of PROVENGE as a first-line treatment followed by the chemotherapy docetaxel upon disease progression may provide patients with a substantially prolonged survival benefit," said Dr. Petrylak.
http://investor.dendreon.com/ReleaseDetail.cfm?ReleaseID=218144&Header=News
I would have also liked to see a breakdown that included comparison of Provenge followed by docetaxel vs Provenge with no docetaxel, in addition to comparison to placebos who crossed over as it appears there were only 82 out of 227 patients who went on to get the chemo after progression in both provenge & placebo treatment groups.
Perhaps this info is derivable from the previous analyses already presently publicly?
By only comparing Provenge followed by docetaxel vs placebo followed by docetaxel, i think this analysis tends to focus on the impact of combined Provenge/docetaxel rather than the impact of Provenge alone (though when you are presenting to a Chemo Foundation, I suppose you don't want to suggest that there is no role for chemo as a treatment option for AIPC).
I do however, like the comparison of the 20.2 month median survival for placebo with docetaxel only (i.e. the 32% who didn't crossover to Provenge) and the 34.5 month median survival for Provenge with docetaxel - more than a year increase.
and Petrylak (who i think was one of the investigators on the taxotere trials) presenting these results doesn't hurt ether.
I came across this news & posted it on IV but thought i would post here as well to see if more scientific types had any comments/reaction to it. sounds pretty promising to this layperson for a rare but deadly cancer. might also have contributed to the increased marekt interest today in immunotherapy stocks such as DNDN & BIOM.
a new study by Dr. Susana Inoges and colleagues at the University of Navarra (Journal of the National Cancer Institute, 98:1292-1301, Sept 20, 2006) has shown that the administration of a BiovaxID(TM) formulation given to patients with relapsed Follicular Non-Hodgkins Lymphoma following chemotherapy, with or without concomitant Rituxan(TM)(1), can induce complete long-lasting remissions. Moreover, these second remissions are uniquely characterized by a duration that exceeds the duration of the first remission (P less than .0001). In the study, 80% of patients achieved an immune response to the Biovaxid formulation, and among these responders, the median time of complete tumor remission has not been reached after 33 months of mean follow-up.
In an accompanying editorial, Idiotype vaccination in follicular lymphoma: knocking on the doorway to a cure, Dr. Dan Longo, National Institutes of Health, characterized the results as "remarkable". "Among the 20 immunologic responders, the median duration of the second complete response has not been reached after nearly 3 years of follow-up (durations range from 20+ to 51+ months) and in every case, the second remissions have been longer than the initial remissions," commented Dr. Dan Longo. "By contrast, all five immunologic non-responders have relapsed, and in every case their second remission was shorter than their first. Long second remissions do not occur at this rate, even after high-dose therapy and autologous hematopoietic stem cell transplant" (Journal of the National Cancer Institute, 98:1263-1265, Sept 20 , 2006).
http://biz.yahoo.com/bw/061019/20061019005553.html?.v=1
the reason I expect Provenge to get an approvable letter on the first review cycle is that 9902a was not genuinely supportive of 9901, and 9901 was obviously insufficient for approval on its own.
so, in effect, you are saying that the pooled data's log rank p-value of .011 with an HR of 1.5 (which suggests that patients who received placebo have a 50% greater chance of dying than those who received Provenge) is not significant/insufficient and requires more data?
sounds like the same type of comment ill-informed doctors have made suggesting that Provenge trial sample size is too small for the results to be considered significant, even though the p-value (log rank) suggests the complete opposite.
DNDN and ridicule.
perhaps Dew's self-imposed sleep deprivation doesn't permit him to recognize his personal obsession so obvious to others?
for his sake, I hope there really are three people posting under his alias.
"Sleep deprivation is an overall lack of the necessary amount of sleep. A person can be deprived of sleep by their own body and mind, as a consequence of some sleep disorders, or, actively, by another individual. Sleep deprivation is sometimes used as an instrument of torture. Sleep deprivation afflicts one quarter of all adults in the United States.
Lack of sleep may also result in irritability, blurred vision, slurred speech, memory lapses, overall confusion, hallucinations, decreased sex drive, nausea, psychosis, and eventually death."
http://en.wikipedia.org/wiki/Sleep_deprivation