Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
Register for free to join our community of investors and share your ideas. You will also get access to streaming quotes, interactive charts, trades, portfolio, live options flow and more tools.
patiently waiting, thank you for posting new Thorpe patent application. VERY interesting stuff. Certainly indicates which direction the anti-phospholipid field is moving. And what a future it appears to have.
sunstar, thanks. Pfizer is a top candidate for PPHM collaboration
yes bungler, I've said all along it is too bad PPHM did not do clinical studies with Bavi in combination with irradiation therapy rather than chemotherapy, but that was what was available then (India and USSR Georgia). We'll really see some headlines when that study is done in humans.
soulofwolf, thanks. amazing article favorable in the extreme for TNT Cotara approach to glioblastoma multiforme
toolong. Good analogy, roulette wheel. It apparently remains too close to call re. the "ifs,whethers,&whats" of Bavi (and Cotara). These initial human trials with naked Bavi will bolster safety profile for anti-PS, a critical long-range trove of information, but it might be a close call re. important survival numbers with Bavi. A close call with the FDA, but probably a favorable outcome there as well. But we know naked Bavi is no barnburner when used an an immunological booster only instead of as an "armed" MAB, packing a payload of cancercidal small particles in one arm while grabbing onto cancer/viral cell-membrane -PS with the other. One solace is PPHM's strong relationship with Affitec which is brewing a much better (humanized? armable?) Bavi, and apparently has immediate clinical trials outlets in Russia.
Anti-TNT therapy (Cotara)has definitely turned a few heads, being able to deliver a punch when injected inside tumor. But like humanizing MAB Bavi, pursuit of a smaller/humanized Cotara is the goal, and that work is proceeding apace. I plan to buy some more shares of PPHM next week (early). All imo.
1st of the month dollar cost averaging early this month...on a dip for a change (I hope)...
north4k MAb Cotara homes in on a component of DNA (actually the spindle around which the DNA winds) called DNA-histone, a component of cell nuclei found in abundance in the center of cancerous tumors. Cancers grow so rapidly that they often outstrip their blood supply, so the central "core" cancer cells become anoxic and die, burst open, and spill their internal elements, which collect in a sterile abscess-like gunk in the middle of tumors of, say, greater than 1cm dia. Interestingly, this central quagmire is a place that 1/2 dead cancer cells can hang out (hibernate), and can reconstitute as a cancer "recurrence" after the danger of chemo-irradiation therapy is past. The reason why these 1/2-dead cancer cells cannot be dealt a death-blow is because of the anoxic conditions. Chemo can't get in where blood vessels don't go, and irradiation is much less effective in such conditions. Obviously, a large MAb like Cotara has some issues getting in there too. That's why intra-tumoral injection is so effective when the tumor is large enough and is not surgically resectable (and this is why cold steel/surgery still has a place at the cancer treatment table.
In re to the new genetic therapy, it would be great to be able to manipulate one gene to prevent metastases, but solving the practical issues of applying the discovery/observation seem a long way off. Hope the above helps.
north40, interesting post. thanks. if only it were so simple! we'll see how it all plays out, but to date a single gene modification has not thwarted cancer. seems there are multiple choices for every body pathway.
achtun carltun...you really believe that? I'm gonna buy some more here pretty quick...mebbee some of yours?
sunstar, thurly,& epistemology. good posts. enjoy and learn from your contributions. thanks.
heychey, you're right, largely irrelevant tidbit of gossip with no real relevance to PPHM. In the light of a new day, upon reflection, it must have been a Chardonnay effect. Snippy not intended. Who was it that said what we need most is a "humor" font for those of us to use who aren't good at it? That said, I remain fascinated by the inter-relationship between academia and big pharma, and especially of PPHM's ultimate patent holders at UTSW and the large voice they have in development and commercial development.
chey, the lady comes from the house that monoclonal antibodies built, Genentec. Any connection between Roche, Genentec, and PPHM? You connect the dots. This is a Roche presentation at the Barcelona meeting Thorpe is keynoting: "Ang-2-VEGF CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functionL
Roche has applied the CrossMab technology to generate a bispecific
human Ang-2-VEGF CrossMab of IgG1 isotype. The Ang-2-VEGF
CrossMab binds and blocks the biological function of the two proangiogenicfactors VEGF-A and Angiopoietin-2. In xenograft models it mediates potent anti-tumoral, anti-metastatic and anti-angiogenic efficacymaking it a promising therapeutic agent for the therapy of cancer. Dr Joerg T. Regula, Head of Protein Analytics, Pharma Research and Early Development (pRED), Roche Diagnostics, Germany".
Friends, I am very pleased to share the news that UCSF Chancellor Susan Desmond-Hellmann, MD, MPH, has just been named among the 10 “most powerful women in Silicon Valley” by the San Jose Mercury News.
The Mercury News compiled the list of powerful women leaders based on three factors: size of their company or organization; number of people under their management; and scope of their influence beyond their company.
Dr. Desmond-Hellmann was listed among other high-ranking women in technology, social media and government and is one of the few leaders with experience in academia and industry.
The Mercury News writes, “In the world of biotechnology and genetics, Desmond-Hellmann was already a towering figure. She played an instrumental role in developing some of the most important cancer-fighting drugs, and then spent years as president of Genentech.
“But in August 2009, she became the first female chancellor at UC San Francisco, an often-overlooked institution despite being one of the region's largest research organizations and the second-largest employer in San Francisco, with a $3 billion annual budget, 4,493 students and 22,196 employees. In her new role, she's now also overseeing the development of UC San Francisco’s massive Mission Bay campus, which will include three medical and research facilities.”
This recognition of our Chancellor is further testament to her incomparable leadership, with which she is guiding UCSF through one of the most important and exciting periods in our history. Please join me in congratulating her on this well-deserved honor.
Carol L. Moss
Vice Chancellor, Development and Alumni Relations
University of California, San Francisco
You are receiving this email because you are a valued friend of the University of California, San Francisco. Please note that your personal information is kept private and is never shared with other organizations.
bigwump, they flipped yovoraG inside-out like -PS on a diseased cell membrane. If anything he's skyped a top security clearance and gone underground...or into a witness protection program.
geo, yes this is a big deal. "How long before we and the market knows it is a can't miss?" That time appears to be approaching more and more rapidly, without significant setback. "Could we get beat to the punch by these others working on the same playing field?" Sure. Nothing is for sure. Not many treatments last forever. Morphine? Aspirin? Digitalis? It Bavi one of those? I think anti-PS technology is pretty enormous. The key is that PPHM has the missiles. They have the human experience. Nobody else has that. Nobody. That spells monopoly. PPHM is the go-to company in this rapidly expanding field. Want to send a mouse colony into space? Go to NASA. Want to send a cytoxic agent to cancers or virally infected cells? Block cancer metastases? Well, that's what Cotara and Bavi are about. The flavor du jour for sure. And now....let's talk about the stock price!!! That involves another entire area of expertise to which I don't pretend to have a clue.[
geo, You asked, "All the companies we saw in the earlier post mentioning Bavi in their patents. What is the relevance of that to pphm with regards to making or not making money?"
My guess: Zero relevance other than as posted previously: that those applying for patents acknowledge they are playing on the same playground.
You also asked, "It seems Dr. Thorpe is showing up more as a speaker discussing PS and its possible benefits. Can anybody relate that to some other medical discovery in the past?"
My guess: Nobel quality.[Wikipedia,on monoclonal antibodies]: "The idea of a "magic bullet" was first proposed by Paul Ehrlich in early 20th century. "If a compound can be made that selectively targets a disease-causing organism, then a toxin [ie, raI] for that organism could be delivered along with the agent of selectivity. Ehrlich and Metchnikoff received the 1908 Nobel Prize for this work which led to an effective syphilis treatment by 1910.
In the 1970s, multiple myeloma was noted to be cancerous B-cells run amuck, and all the cells manufactured a single type of antibody (a paraprotein). This discovery spurred the study of the structure of antibodies. .
Production of monoclonal antibodies involving human–mouse hybrid cells was described by Jerrold Schwaber in 1973, and his process remains widely used in making human-derived hybridomas. Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975 shared the Nobel Prize in Physiology or Medicine. . The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody-producing B-cells, and be able to select for the successfully fused cells.
In 1988, Greg Winter and his team pioneered the techniques to humanize monoclonal antibodies,[5] removing the reactions that many monoclonal antibodies caused in some patients.
Correct me if I am wrong, but Thorpe recognized and has now realized the therapeutic potential of a monoclonal antibody directed at a cell membrane site which flips inside out in virally infected and cancerous cells. It was accidentally recognized that the same antibody directed at that -PS membrane site somehow enhanced immune attack by the body's monocytes. It was then discovered that -PS exposure on diseased cells inhibited scavenger cells and encouraged disease, blocking the body's immune response. Originally the idea was to follow Erlich and Metchnikoff's idea of specifically targeting cancer with a specific antibody capable of homing in on cancer cells and carrying cancer killers with it. That is exactly what "armed" Bavi is capable of, because it is double armed. At this point the fully armed fully humanized Bavi apparently has some specificity problems which will certainly be ironed out. Loading one arm of Bavi and blocking one of its docking site to -PS apparently decreases the MABs affinity to diseased cells. So we have Cotara that delivers radioactive Iodine, a known cancercidal, deep within tumor. Its problem is the size of the missile, not fully-human, with some bone suppression issues. And we have Bavi-, so far an immunological adjunct, or stimulant, because of the newly discovered role of phospholipids in cellular death and clean-up.
thanks mojo, nice work
PPHMownsme, the .10 dips at opening (and variations thereof) always remind me of fishing. MMs throw out a lure, or a net, the previous session, and then pull in the chump who bit at a higher price and placed tight stop losses.
carltun,thanks. great resource. I "cut,copy,pasted" it, and with success this time.
lafont, agreed. Stock price soars when all the money players are satisfied with their cut...not before. This is so enormous that PPHM will be around for a long time now. Its no longer a matter of survival. Hasn't been for a long time because of PPHM properties. Many deride management, but one of their biggests tasks has been (and remains): how to thwart those who would steal the tech.
To make money when you're new in the game you have to give some away...China Cotara comes to mind. And how about all the free flow of information about TNT-Cotara anti-DNA histone technology out of that country?
The clinical application fo both technologies, TNT and anti-PS is quite strong IMO. PPHM's wisdom in licensing 2C3 ("the better Avastin") to Affitec appears wise, after looking at what Roche has coming down the pipeline.
apologies for the faulty "cut,copy,and paste job." It was "Hoorah for team PPHM." What a noteworthy improvement with all you new guys around to help with the heavy lifting. Keep up the great work!
cj, quite a lot of info. in that Barcelona MAb Conference folder. I can't afford the $6000 admission ticket, otherwise would be tempted to go. Reading the abstracts is a "consciousness raiser" for those into MABs, and where we're going. The following Thorpism bears parsing imo.
"Bavituximab is a therapeutic monoclonal antibody that is in clinical trials in lung cancer patients [a clue to when abstract was submitted, and how far we've come in only weeks...{how about a much deserved, "HoIt targets the immunosuppressive lipid, phosphatidylserine, which becomes exposed on tumor blood vessels & tumor cells. Bavituximab causes macrophages to polarize into tumoricidal M1 macrophages that destroy the tumor vasculature & tumor cells by ADCC. In addition, it stimulates the generation of tumor-specific cytotoxic T-cells.”
orah" for team PPHM}...)
"...[Bavituximab]... becomes exposed on tumor blood vessels & tumor cells...?
"...Bavituximab causes macrophages to polarize into tumoricidal M1 macrophages that destroy tumor vasculature & tumor cells by ADCC.
{ADCC def. Wikipedia: Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) is a mechanism of cell-mediated immunity whereby an effector cell of the immune system [ie monocyte] actively lyses [bursts open] a target [cancer or virally infected] cell that has been bound by specific antibodies [-anti-ps].
It [ADCC] is one of the mechanisms through which antibodies, as part of the [body's inate] humoral immune response, can act to limit and contain infection.
Classical ADCC is mediated by natural killer (NK) cells; neutrophils and eosinophils can also mediate ADCC. For example, eosinophils can kill certain parasitic worms known as helminths through ADCC.
ADCC is part of the adaptive immune response due to its dependence on a prior antibody response.
TAKE AWAY: 1) Bavi- facilitates the tumor-cell bustin' ability of M1 macrophages. 2) anti-PS strategies are lookin good. And there are some interesting "others." Read the Barcelona Meeting Abstracts.
In addition, it stimulates the generation of tumor-specific cytotoxic T-cells.”
cj:re.Thorpe Barceona Conf in May. No more graphic display of PPHM ascendant status within the therapeutic community is possible than to see him as a keynote speaker at the 10thAnnual Barcelona Recombinatnt (MAB) conference. He was selected by the foremost European scientists for that, and the positioning of his 50 minute talk, opening the third and last day of the conference, is definitely in the conference's catbird seat for holding and pulling in audience. Additionally, he is doing a day-long seminar: "A-Z of Therapeutic Antibodies"
'Speeding Manufacture and Development from Discovery to IMP
Registration: 08:30 | Start: 09:00 | End: 15:30 | Refreshments and lunch will be provided
This workshop will provide delegates with an in-depth overview of the processes involved at every stage of the drug discovery process of therapeutic
antibodies, with practical advice from a range of experts from academia and industry. In addition to hearing key speakers present their points-of-view on this
topical area, delegates will have the opportunity to discuss the issues and exchange ideas and strategies.
Topics include:
• Dose-setting proposals • Strategies to achieve pre-clinical safety
• Study design in an academic setting • Changes in the use of animal models
• Optimising in vitro tests • Document preparation
• Use of analogue surrogate molecules in pre-clinical testing • Risk assessment guidelines
• What do the regulators require?
Workshop Leaders:
Dr James W. Larrick, Scientific Director, Panorama Research Institute (PRI), USA
Dr Philip E. Thorpe, Professor of Pharmacology and The Serena Simmons Distinguished Chair, University of Texas Southwestern, USA
Dr Dimiter Dimitrov, Senior Investigator, National Institute of Health, USA
Dr Muralidhara Bilikallahalli, Principal Scientist, BioTherapeutics R & D, Pfizer, USA
Dr Sophia Karagiannis, Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, UK
cj: thanks for the reminder information re. PPHM's P.Thorpe, and for all you other considerable kindnesses.
carltun, I agree it is looking better for trading PPHM, but if and when I begin trading short-term, it will be with a large core-holding behind the poker table stakes I'm having fun with, and unfortunately I am still rebuilding core holdings after the reverse split. Another way we differ is my core holding of PPHM shares represents my evaluation of the company's core holding, and not simply the prospects of Bavi or Cotara. I believe PPHM has the bench strength to survide as a company at last. Now we aren't talking survival as a corporation, but elegance of survival. Hopefully it will also bring not only survival to cancer patients, but more elegant survival with less colateral damage from treatment.
pphmtoolong. right on, hope you're right.
Carltun, welcome (back) to the board. You defined investment and speculation for yourself, labeling PPHM speculative, which seems a reasonable definition. But don't think that definition necessarily works for others. Dollar cost averaging into a company you believe in is another way to invest, and obviously a good way to it at a time like this when share price appears to be rising. All kinds of people with myriad strategies come to the marketplace, and almost all have an hypothesis about how they will thrive while most fail. And while agreeing that PPHM remains speculative, it becomes incrementally less so almost daily.
I'm not so certain the company would evaporate without Bavituximab, as one poster suggested. The most valuable asset is the company's primacy in anti-PS therapy...priceless...the value of owning a whole realm of proven treatment, a whole new therapeutic field. If Tarvacin fails, or is sold, it would not be fatal. PPHm and Affitec are ramping up "a better Avastin" a fully humanized anti-VEGF. And then there is Avid, PPHm's fully owned subsidiary that manufactures FDA approved MABs. PPHM has huge experience in small molecules, such as TTF (truncated tissue factor), and PPHm ownes TNT tumor necrosis therapy, with MAB missile Cotara that docks on necrotic celluslar DNA-Histone at the center of cancers where where malignant cells can hide dormant, and then return after chemoirradiation therapy. Cotara goes to the center of tumors where it releases radioactive ioding whichs diffuses out from the center in all directions, toward the surface of the cancer where an anti-VEGF and antiPS agent are at work. So Cotara-like MABs will be used to kill core cancer cells; antiVEGF and anti-PS agents will kill surface cells by unblocking the immune system, and starving cancers of their blood supply. All this was a dream less than a decade ago.
Dew I think you should drop it. You're beating a dead horse with an opinion that is interesting and post-provoking, but the reality is that even if we keep interferon in the mix, a sizable proportion of patients exposed to it cannot tolerate it. Maybe there's room for another entrant? Labeling the Bavi unethical seems a bit strong.
Cruisin' at $.60 pre-split. Margin-HO!
Dew, interesting concept, but questionable legs. As added perspective and review for those in this discussion:A Cochrane Review: Ribavirin monotherapy for chronic hepatitis C by Brok J, Gluud LL, Gluud C
Treatment of patients infected with hepatitis C virus
Globally, about 170 million people are chronically infected with hepatitis C, a blood-borne virus transmitted by intravenous drug use, mother-to-infant transmission, unsafe medical practices, high-risk sexual behaviour, and blood transfusion. Chronic hepatitis C is mostly a benign viral infection, but a minority of patients develop liver cirrhosis and may suffer from complications due to cirrhosis or die from it.
Interferon monotherapy clears hepatitis C virus from the blood in about 15% of patients. Adding ribavirin to interferon (combination therapy) significantly improves the number that clears hepatitis C from the blood to about 30-40%, but the majority are not long-term responders, and many cannot tolerate interferon. Not all patients can tolerate interferon, and also interferon is costly. This review identified 11 randomised trials comparing ribavirin with no antiviral treatment in patient with chronic hepatitis C. Combining the results from all identified trials ribavirin alone seemed without beneficial effects for patients with chronic hepatitis C. Moreover, ribavirin given alone was significantly inferior compared with interferon regarding clearing hepatitis C from the blood and regarding reducing liver enzymes activity in the blood. Furthermore, ribavirin given alone increased the risk of anaemia. Thus, ribavirin given alone cannot be recommended, but more trials may be needed."
Additionally, resistance to Ribavirin occurs frequently in spontaneous mutations in both hepatitis and polio virus infections.
threes. too funny. megadittos. eom
geocappy, dart as white knight doesn't pass the sniff test, but then I can't figure how anyone buys (at least) 7% of a company stock if they want the price to go down. And hey, this last info burst about dart from y'all makes me proud to be a part of this deliberative thread. S'pose it's so simple as guessing where his exit price is going to be? If we keep this up he might opt to sell on Monday!
jess, good question, but does it matter? As a physician I should be well-versed on poison pills, but I need a primer here. Tell me if I am wrong, but if poison pill provisions are triggered, isn't the option for more shares at current price simply a hedge? And doesn't it in some ways discourage disgruntled stockholders from filing a suit because management gives away the store at a price lower than true value?
pphm too long, the problem is these people can significantly move the stock price (and probably have) at a whim. They've floated a huge amount of our cash into their pockets just since the reverse split, to go back only a few months. And then we can go back further...years...all that talk about Caribbean money picking our feathers clean. There's one way we'll make money in this stock, and it relates to quality of product, not manipulators. The Darts are on board because the science platform is compelling. Really, how can they lose?
swg, fascinating. thanks. lots of landmines on the way down the drug pipeline.
frustrated, I share some of your feelings, but the reality is that uptown $80k/year is a give away for guys with huge talent...charity work...peanuts...a get together for guys devoted to the cause..all that. Not a huge number, 80k. It's true, not a lot of physical labor involved, but my guess is that they are worth it. And $80k is not even much dough for medium hitters in the rarified atomosphere of today's board directors. Look at what the competition offers.
cash2go,helpmeouthere. Who were the double-licensees? And, it was a given at the time that we give away Cotara in China in lieu of that country doing the clinical research on the drug. And that China strategy launched in 2002(?)seems to be solid at this point.
Jess,author of this 06 -TNT article, "Like Yu":
http://www.liebertonline.com/doi/abs/10.1089/cbr.2006.21.5
Cancer Biotherapy & Radiopharmaceuticals
131I-chTNT Radioimmunotherapy of 43 Patients with Advanced Lung Cancer
Like Yu
Nanjing Pulmonary Hospital, Nanjing, China.
Dian Wen Ju
Shanghai MediPharm Biotech Co., Ltd., Shanghai, China.
Wenping Chen
Nanjing Pulmonary Hospital, Nanjing, China.
Tian Li
Nanjing Pulmonary Hospital, Nanjing, China.
Zhaoqiang Xu
Jiangsu People's Hospital, Nanjing, China.
Changying Jiang
Tumor Hospital, Shanghai, China.
Shaoliang Chen
Shanghai Zhongshan Hospital, Fudan University, Shanghai, China.
Qun Tao
Shanghai MediPharm Biotech Co., Ltd., Shanghai, China.
Dan Ye
Shanghai MediPharm Biotech Co., Ltd., Shanghai, China.
Peisheng Hu
Keck School of Medicine at the University of Southern California, Los Angeles, CA.
Leslie A. Khawli
Keck School of Medicine at the University of Southern California, Los Angeles, CA.
Clive R. Taylor
Keck School of Medicine at the University of Southern California, Los Angeles, CA.
Alan L. Epstein
Keck School of Medicine at the University of Southern California, Los Angeles, CA.
The treatment of advanced lung cancer remains a major challenge in clinical medicine, justifying an urgent need for new therapeutic approaches. In a rather unique international collaboration, 43 patients with advanced lung cancer were treated using iodine-131-labeled tumor necrosis therapy chimeric antibody (131I-chTNT). Methods: Patients were treated either with intravenous (i.v.) infusion (n = 22), intratumoral injection using a computer tomography (CT)-guided catheter (n = 16), or combination i.v. and intratumoral infusion (n = 5). All patients, regardless of route of administration, received 2 doses of 131I-chTNT on days 1 and 14. Results: The results showed that of those patients receiving i.v. injection alone, 2 achieved partial response (PR) (9%), 16 had stable disease (73%), and 4 progressed (18%). Of those patients receiving intratumoral injection only, 1 had a complete response (CR) (6%), 8 achieved PR (50%), 7 had stable disease (44%), and none (0%) progressed. Finally, of those patients receiving both i.v. and intratumoral administration, 1 had a CR (20%), 1 achieved PR (20%), 2 had stable disease (40%), and 1 (20%) showed progression. Conclusions: These promising results demonstrate that sufficient doses of radiolabeled antibody can be safely delivered to tumors to cause significant therapeutic effects in advanced lung cancer.
***Jess, the agreement is for a murine (Mouse) clone. Suppose that includes fully humanized (as opposed to mouse) -TNT MABs also?
note approx. 20% of cancer cells survive in this model. A certain application for Cotara. And "holistic prevention"??? Try this one: Appealing in its simplicity. Oh, that it is all so easy: Iodine Deficiency and Cancer Question: Is there a connection between iodine deficiency and breast cancer?
Dr. Brownstein’s Answer:
Iodine has been found to be necessary for the maintenance of normal breast tissue. The connection between iodine deficiency and breast cancer, as well as fibrocystic breast disease, is strong, and recent research is making this connection even stronger.
Breast cancer (like prostate cancer) is occurring at epidemic rates — currently one in seven women are affected. Prostate cancer affects one in three men. Although there are numerous reasons for the development of cancer, the research is clear; iodine deficiency is a major piece of the puzzle. Iodine deficiency has also been associated with other cancers including ovarian, uterine, and thyroid.
Perhaps the reason we have made so little progress in our treatment of nearly all of the hormone-sensitive cancers is that the underlying cause has been overlooked. This underlying cause could very well be iodine deficiency.
It is imperative to have your iodine level checked and supplemented with the correct form of iodine when there is iodine deficiency identified.
I feel iodine status should be investigated in all cancer patients. The best results with iodine therapy occur when iodine supplementation is given as a part of an anti-cancer program.
© 2010 Newsmax. All rights reserved.
about Dr.Brownstein;https://www.drbrownstein.com/homePage.php
Interesting article in SCIENTIST Daily:By Megan Scudellari. Cancer's shield seen, stripped Researchers find - and reverse - tumors' ability to hide from the immune system [Published 4th November 2010 06:00 PM GMT] Researchers have identified how cancer escapes detection by the immune system -- support cells surrounding a tumor protect it from triggering an immune reaction. The research, published this week in Science, may ultimately provide a new therapeutic target to activate the body's natural defenses against malignant cells.
"The beauty of this article is that it clearly connects certain stromal cells of the tumor microenvironment to the immune system," said Hans Schreiber, an immunologist at the University of Chicago who was not involved in the study. "It was very well done." Researchers have long wondered how cancer evades attacks by the immune system, trained to recognize and destroy all foreign material. In the past, even when an immune response is mounted in an animal with cancer, the tumor itself remains relatively unscathed, since neighboring immune cells fail to attack. "It was something going on inside the tumor that was suppressing the immune reaction," said Douglas Fearon, an immunologist at the University of Cambridge and senior author on the paper.
Cancer cells sit in a bed of nonmalignant connective tissue called stroma. Fearon and colleagues hypothesized that a subset of stromal cells expressing fibroblast activation protein (FAP) might be involved in keeping the immune system at bay, since FAP expressing cells are also present in the uterus, placenta, and areas of chronic inflammation, all locations where the body is trying to subdue or control an immune response. The team bred transgenic mice with a genetic switch to kill FAP expressing cells when exposed to diptheria toxin and injected the mice with tumors. Two to three weeks later, when the tumors were well established, the researchers eliminated the animals' FAP+ cells.
Within 48 hours, the mice had mounted an immune response that killed 80 to 90 percent of the tumors. As a control, the researchers performed the same experiment in mice without an immune system, and removing the FAP+ cells had no effect on the tumors. "We had to combine both depleting FAP+ cells and an immune response to the tumor," said Fearon. "That proved that the tumor death caused by [loss of] FAP+ cells was mediated by the immune system."
The team is planning to validate their findings in a spontaneous tumor mouse model developed by researchers at Cancer Research UK, one that better models tumor development in humans.
The paper demonstrates that FAP+ stromal cells are an important target for cancer drugs, said Schreiber, who wrote an accompanying perspective in Science. But though antibodies already exist for FAP, the challenge will be targeting drugs to the cells without affecting the many other nonmalignant cells that express FAP, he cautioned.
But if researchers can determine how the FAP+ cells are getting to tumors or how they suppress an immune response, they may be able to either block the cells from getting to a tumor or from suppressing the immune system once there. "At least now there is a very specific cell type we can analyze that might be accounting for suppressing immune reactions in a tumor," said Fearon. "It's a step."
Kraman, M. et al., "Suppression of Antitumor Immunity by Stromal Cells Expressing Fibroblast Activation Protein-alpha," Science, 330:827-30, 2010.
Related stories: A cancer vaccine -- that works?
[25th November 2009] A complement for cancer?
[29th September 2008] Is autoimmunity like cancer?
[2nd February 2008]