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jakedogman1, greatly appreciate the articles, which were well-written, and bring us all up to date on the Opdiva/Keytruda competition. Like PPHM, we remain clueless regarding trials which we, the stockholders pay for. This is only one tragedy identified in a ruthless "war on cancer" waged for profit since the days of Richard Nixon (and earlier). What do the pathology slides show in Bavi patients? How much of the MAB IS, in fact, seen in tumor vasculature, and tumor, and other places in this test? These kinds of questions, and their answers, are what I am looking for. Now I wonder if the Keytruda results were falsely high in light of the Opdiva subgroup analysis. I am sure BMY is going to be stratifying responders and non-responders on the percentage of PD-L1, yada. I an be double miffed because I own BMY also! Read my lips: Immune-Oncology treatment of advanced lung cancer is a pipe dream, and might help a precious few, which is interesting. The spin-off information gleaned with this (and the Bavi trial) will keep a lot of immunologist busy for a few years.
cloaked, I don't get it: You said, "If Bavituximab would not work (which is certainly still an option for those that do not understand it in depth as I do now), then there is no "stall in a well-financed stable..." as endoc worded it for bavituximab."
You must have meant, "If Bavi does not work for I-O?" And as for understanding it in depth as you do now, you say there is no place for Bavi for any application?
The logic of these posts is often very difficult for me to follow, but then they might be more understandable for those who understand Bavi in such depth as you do.
My point is, and always has been, that it is nonsense to expect Bavi to impact end-stage lung cancer. I haven't said that about cancers that are detected in, say, a sub-centimeter size. Antiphospolipid antibody inquiry seems sensible to me in many other applications than immune-oncology, and PPHM certainly has a lead in that sector. The rapid expansion of peer-reviewed articles in that space speaks volumes. Cheers!
JCNJ, seems logical. The problem is, and always has been, agreeing on a value for Bavi. There is increasing competition out there every day re. exclusive docking sites, etc. cheers!
hope filled, methinks the handwriting on the I/O wall has been fully comprehended as it applies to advanced NSCLC. Actually, all these trials provide us with valuable information, but the incremental good vs. expense, and the possible negative PR for both products, could easily be judged to not be worth the price of admission. Imagine Durvalumab/Bavi combo being worse than SOC, etc. etc. I think the next thing for bavi is to find a stall in a well-financed stable that can afford to be in the race for the very long run. If PPHM continues to sit on Bavi, and if PPHM can move forward with Avid, Bavi will either emerge in the distant future with a role in chronic inflammatory conditions and early cancers, or be shelved for some long time.
yes catboat, agree, does not look as if Bavi for large incurable solid tumors is the answer It is looking like the MAB construct known as Bavituximab is safe. Bavi is a vehicle. Its carrying capacity or payload delivery is still in question. That leads us to fully humanized Bavi, the one I prefer. But Dr. Thorpe liked Bavi 1/2 half mouse and 1/2 human. More antigenic he said. That is one major area of departure for Dr. Thorpe and me. I have my heart set on more fully humanized Bavi. By-the-way, where are we with that construct last being tested in Russia?
solace, REALLY like this post. a classic. thank you.(read it twice!)
cloaked, if only scientific realities were as easy to establish as writing about impressions of incomplete and short-term data. The landscape is strewn with safe medications that later prove to be the opposite.
It does appear that Bavi is safe, but my questions also relate to termination of PIII. As you well know, there are "insider" ways of taking leave, especially when asked politely to leave for unpublicized reasons. I want to be sure we are not "papering over" some other issues. The anti-phosphatidylserine syndrome, for instance is real. What dose of Bavi triggers thromboembolic events? If any. You have a very good grasp of most the scientific principles, and I salute you for that. However, until you've held a lung cancer in your hands you do not really have a clue about the enemy we are up against. Cheers! And thank you heartily for all your valuable input here.
catboat. I am a scientist. Help. How do we know they are selling shelf shares?
revenue monster, almost certainly SK said he THOUGHT there would be a synergy between Bavi and Doce. Remember, that is why clinical trials are run. He looked me in the eye and said, "I believe Bavi works", and it is looking more and more as if he will be right. Not, incidentally like a stopped clock that is right once or twice a day. We'll see if the Patriot Science crowd has learned how to do a licensing deal.
Hi James. The tenor of my recent questions re. side-effects was an effort to pin down with some increased certainty that "futility" is not an euphemism for some other reason to discontinue the study., and that Bavi is, in fact, reasonably safe for less dire diseases than advanced, incurable lung cancer. If Bavi prolongs life a few days, weeks, or months in lung cancer patients, who am I to say how much an individual or society should pay for that. Is the increased survival with Bavi, which could be more of a statistical event than a real-life improvement, worth the price? Insurance companies are probably not going to buy it. Would it be "standard of care", and everyone would get it? Doubtful. Bavi could be used "off-label", but, again, no insurance company is going to pay for that. I think it best that we take our preclinical and human data points to another disease entity. -PS has had uniformly good "scientific press". How are we going too get there? Licensing to big pharmas that can afford to run the clinical trials. How is the company at negotiating licensing deals? Will there be any demand for anti-PS, or anti-PE, or anti-any other anti-aminophospholipid? It seems to me logical that there will be a demand for such MABs, and Avid is ready to produce them. If the track record of Patriot Scientific, with much the same BOD, and with a stable of interesting patents, and not much business, is a bellwether, we could be in for some cloudy weather.
for the -PS docking site "sink" folks aboard, not all the body's immune holes must be plugged by Bavi for the body to stay alive or afloat. We tend to think in terms of all or none, but the reality is that a simple little boost to the body's immune system (with Bavi), regardless if it is soaked up by the overwhelming number of body -PS receptor sites, is sometimes the difference between life or death. Only a little dab will do you sometimes. Also remember, if there is a -PS sink, how much of it can be filled by Bavi? and at what rate. We still have some dosing info to obtain
Most of the FDA required'heavy-lifting' for Bavi s done. Bavi being safe is huge. Not the whole enchilada, but safety is critical...do or die for a pharmaceutical upstart. Efficacy would have been nice too, but Bavi vs. advanced lung cancer? Not a chance. As an immunological adjust to chemotherapy? An oxymoron...non-sequitur? Note: Bavi + chemo is mostly what our options were back then. Safety opens vast new horizons for Bavi. Who can wait around for results of Bavi plus surgery for early stage disease? We want Bavi results NOW. No time for long-term outcome of Bavi +irradiation...and that is irradiation of almost any stage cancer. And do we have the time or money for the probable best place for Bavi? Given before, during, and/or after surgery...for almost any disease being approached surgically. Irrigate the wound with Bavi, etc. etc. Bali is absorbed through the nasal mucosa. Add it to your favorite nasal douche. I can understand why they have bothered with a Bavi trade name. Bali even has a new manufacturing plant ready to clone it. Now all we need is an application for Bavi, and I suspect that will happen. Think of all the myriad possibilities with Bavi. Curing advanced lung cancer with Bavi was a pipe-dream. The company got what it was after. If not efficacy, then at least information. Question is, will we stockholders be a part of the Bavi boom.
veets, read my lips: IO is a farce for large solid tumors. IO is the early game, not the end-game. BP is going to school on the money of every one of us investors and patients. Hopefully the spin-offs will be worth the price tag. Treatment for terminal large solid tumors is definitely not worth the cost. It is still surgery, irradiation, or chemo. I can even go along with IO for helping survival stats for surgery and irradiation. Trying to use an immunomodulator/immunostimulator when poisoning the immune system with chemotherapy is just plain nuts. So are those MSK ads...or maybe one should listen more carefully to the claims.
SK mentioned Bavi and Alzheimer's disease 3 years ago at a stockholder's meeting. The following is a good summary of the role/presence of exosomes in neurodegenerative disease, heart disease, and other inflammatory processes. The biggest problem I see with Bavi and exosomes is specificity. We'll see. I think the point of all this is that PPHM has a firm handle on research and patent protection for the entire anti-phospholipid platform, and is in a position now to license and manufacture anything any pharma wants to tinker with in that realm.
google "exosomes in Alzheimer's disease, and click on the following:
Novel clinical applications of extracellular vesicles: - Page 10
https://books.google.com/books?isbn=2889196453
Matías Sáenz-Cuesta, ? David Otaegui, ?Maria Mittelbrunn - 2015 - ?Preview
Exosomes. Associated. to. the. Generation. and. Progression. of. Neurodegenerative. Diseases. Exosomes have been ... characterized in other neurodegenerative diseases like Alzheimer's, in which tau protein aggregates form filamentous ...
cj, thanks for info re Bavi and exosomes which are markers for cancer.
Title: Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine Dependent Arrest in the T Cell Signaling Cascade
Authors and Affiliations:Raymond J. Kelleher Jr.1, et.al
Abstract The identification of immunosuppressive factors within human tumor microenvironments, and the ability to block these factors, would be expected to enhance patients’ anti-tumor immune responses. We previously established that an unidentified factor, or factors, present in ovarian tumor ascites fluids reversibly inhibited the activation of T cells by arresting the T cell signaling cascade. Ultracentrifugation of the tumor ascites fluid has now revealed a pellet that contains small extracellular vesicles (EV) with an average diameter of 80nm. The T cell arrest was determined to be causally linked to phosphatidylserine (PS) that is present on the outer leaflet of the vesicle bilayer, as a depletion of PS expressing EV or a blockade of PS with anti-PS antibody significantly inhibits the vesicle induced signaling arrest. The inhibitory EV were also isolated from solid tumor tissues. The presence of immune suppressive vesicles in the microenvironments of ovarian tumors and our ability to block their inhibition of T cell function represent a potential therapeutic target for patients with ovarian cancer.
Cloaked, interesting thread on Garnick. thanks. I continue to stand in his corner on Bavi. If it (or similar anti-phospholipid MABs do not have a therapeutic application I will be surprised.
I'm still thinking over the recently published info. about Bavi side-effects, but tend to agree with most of your speculation that it is safe and well-tolerated, which is huge, and (next to efficacy) is one of the most important bits of information to be gleaned from clinical trials of any new compound. We also need to learn about the individuals, if any, from the aborted trials (both PII and PIII) who are still receiving Bavi.
My motive for closely examining what has been disclosed about side-effects noted during the two trials is to assess how reasonable it is to consider Bavi for other anti-inflammatory applications, and how difficult it will be to receive FDA approval to launch such trials Advanced solid tumors applications are out. Always have been IMO. There are myriad potential applications, though, for Bavi: inflammatory states and subclinical/< l cm solid tumors. to mention only two. In other words, as stockholders we need to be vigilant about not allowing the platform to be given away.
In this business of clinical trials what we learn about possible"spin-off" applications of a "new discovery" is sometimes more important than what we learn about the original intended application.
As noted, a MAB for advanced solid cancer (lung) continues to be a pipe dream. Such an application was expecting a bit too much for Bavi.
BioBS...thank you for the May, 2016 article eb0783. check it out. Bavi side-effects. I will study the data and see which side-effects can be teased out of the data as attributable to Bavi. Cheers! .
Anyone here know anything about Bavi side-effects? Anything out there? Anyone?
Nobody interested in Bavi side-effects?
exwannabe: nice...." sifting thru data" should include what Bavi-effects on human lung cancer tumors look like under the microscope...if the treated tumors look anything like what we have seen in lower animals. I imagine (hope) that data is out there. Has anyone seen it?
Again, has anyone on this board actually seen a comprehensive statistical data analysis of Bavi side-effects? It is axiomatic [in the trade] that for a pharmaceutical agent to have "effects" it must also have "side-effects". Of course there are exceptions to that saying. If anyone has seen this data I would appreciate you posting it. Thank you.
Cloaked, you wrote; "Are you saying that AstraZeneca is going to run the Durvalumab+Bavituximab combo clinical trial, which is a immuno agent combination, in NSCLC just for the show. Because under your statement below that is all what is would be." Those are your words, not mine. AZ need sampan' that will make Durvalumab work. We'll see. I'm sure some of the AZ and PPHM scientists will learn from it. I'm not so sure we will learn or profit from it. Don't get me wrong cloaked, I am still invested here, and would love for lightening to strike, whether it is with durvalumab or another. The only way we'll know if it adds a few months of life is to try it...with a statistically more cooperative control group.
James, here is a "real-time" lightening strike map. Take a look. Not a single one in California. https://www.lightningmaps.org/#m=sat;r=0;t=3;s=0;o=0;b=;n=0;y=37;x=-100.0762;z=5;
Of course California has lightening strikes, but few compared to the upper mid-west. My point is, and has been for years, that no immunological agent or combination of agents is going to back off advanced lung cancer. such could conceivably hold it off after surgery, irradiation, or standard chemotherapy. Bali is going to be best used in early cancers, and to prevent cancers, mostly through anti-inflammatory properties. You need to hold a large lung cancer in your hand sometime...or at least see one up close. Miracles happen. We've all heard of at least one. Just like lightening strikes in California. On another subject...again...has anyone asked for an immune-pathology report gleaned from this study, or any pathology report to see what Bavi did under the microscope? Pretty important stuff. How about a detailed side-effect analysis? I hear rumors about freedom from side-effects, but have not seen a detailed statistical analysis of, say nausea, bleeding, headache, rectal itching. It seems we have a lot to learn, and there is zero information forthcoming, ir indications that it WILL be forthcoming...e.g. the "subgroup analyses". who gets to see that, and when?
Vinmantu, I was not hedging, but leaving open the small (small to the vanishing point) chance that Bavi could be used in combo with other immunology-oncology agents for advanced lung cancer. As usual (and as said before), the people who really understand what is going on are those who have the postmortem target tumor on a slide, stained appropriately, under a microscope. That tells a story that theorizing on the number of -PS receptor sites left open after Bavi dosing will not tell. Cheers!
cj, thanks, as always. do you really think the FDA is going to approve a drug for a given indication when the trial for that indication was stopped "for futility"? I am not saying it is impossible, but I am saying that I would not buy any more stock on that premise. Lightening can strike almost anywhere (but California).
IMO there is an extremely slim chance Bavituimab is going to be used OR approved for treatment of advanced lung cancer. It simply does not make sense to me. I won't belabor the board with my usual diatribe against immunology-oncology applications in advanced cancers of "anything". I do think Bavi (TALCAEPTRX) might eventually have an application as an anti-inflammatory agent, and since cancer is now widely believed to be a response to chronic inflammation (in many/most? cases), then its early use might have cancer-preventative applications. Cheers! ENT doc
mass hysteria, thanks for the post. Do you really think immunology-oncology is going to cure large solid cancers? the hope for Bavi seems to be what happens with scientists going down one alley, and finding themselves on a boulevard...or a dead-end street. the best thing about Bavi? the staggering (now) amount of pre-clinical and clinical (human) data we have on safety. What I see as the most likely outcome, pending use of Bavi in very early (millimeter-diameter to centimeter diameter tumors), is the spin-offs. Here's one of many paradigms. A patient with Altzeimer's and advanced lung cancer; or rheumatoid arthritis; or diabetes...and it is noted that tumor grows, shrinks, or stays the same, but one of the patient's other disease processes significantly improves. There are many scenarios for outcomes of "sub-group analysis", but I, for one (as you all know) am ready to let the big pharmas duke it out for large solid tumors, and will settle for something as prosaic as significantly improving the common cold, or sinusitis. keep your fingers crossed. it seems we stockholders will be the last to hear about it.
patiently waiting & hutch, thanks. I-O not "a joke", but not a "bargain for the buck" either. I am encouraged that Padzur, et. al. want to move with it toward earlier intervention. I see iI-O as similar to cardiac bypass for the {innocent] immune system during or pending definitive treatment , and as definitive tx. when dealing with very early disease. No question in my mind that Bavi- will have an application. Still thinking of Alzheimer's Disease now that we are closing in on earlier diagnosis.
Worldwide production of MABs by 2020 is projected at $125 billion, and PPHMs share of that should increase proportionately, if not faster. PPHM shift to MAB manufacturing is a very wise business decision, and obviously a sea-change in the company's direction. PPHM has put several MABs out there for consideration, and has patent protection on many other potential MABs in the antiphospholipid MAB space which, if proven effective in some therapeutic capacity, can easily be manufactured by Avid. There is no question in my mind that Bavi-, as such, has limited value in treatment of advanced solid tumors. However, I do believe it probably will have therapeutic value in preventing growth and development of early solid tumors, and possibly in other chronic inflammatory states, and that PPHMs entire aminophospholipid platform and patent portfolio has value. As mentioned here several times, I have been involved peripherally in, and followed the I-O field since 1970, when BCG was being investigated as a "non-specific immunological adjunct", and with only a few exceptions for solid tumors, not much progress has been made in nearly a half century. The deck is loaded against any I-O agent in trials against patients with advanced solid tumors and already compromised immune systems. If Bavi is successfully coupled with other agents in the I-O field, and causes only an incremental improvement in survival, who will be able to afford the price of two agents for a short increase in survival? If Bavi is going to be used successfully it will probably be used when sub-centimeter diameter tumors are detected by blood tests rather than imaging. It is also possible/probable that Bavi- could significantly improve over-all survival in cancer surgery and irradiation. I would love to be proven wrong about much of the above because I am still heavily invested, but there appears to be considerable wishful thinking here about Bavi- despite hard, cold facts.
MAbs. 2015 Jan-Feb; 7(1): 9–14.
Published online 2014 Dec 20. doi: 10.4161/19420862.2015.989042
PMCID: PMC4622599
The therapeutic monoclonal antibody market
Dawn M Ecker, Susan Dana Jones, and Howard L Levine*
Hey wook and north: FAB u-tube video on Peregrine Falcons, both parts I and II. a "birder" delight. thank you.
Maybe we can now go back to fully human Bavi-, and get past the "more immunogenic" chimeric Bavi?? I think even Dr. Thorpe, a Bavi inventor, was wrong about which form of anti-PS MAB would be more clinically important: fully human or chimeric.
the other guy, the question (at least to me) is not whether radioactive iodine is cancercidal and a good treatment modality (it is), but whether and what type of MAB is necessary to deliver it. If you have to place a catheter into the cerebral spinal fluid space, thread it up to the tumor, or put a hole in the skull to thread the catheter into the subarachnoid space...and then penetrate the tumor...and then deliver the I-131, do you really ned a monoclonal antibody to deliver it!?! The point is to find a MAB that will cross the blood-brain barrier (almost an oxymoron). "Homing-in on the -PS of the tumor vasculature with Bavi ,and then lobbing the tumorcidal agent at tumor interior...AND surface...is what makes sense. I can see stopping GBM dead in its tracks that way. But so far we have made all the wrong choices for clinical trials: Chemo- + Bavi instead of Irradiation + Bavi. AND THEN we move toward immune-oncology...I-O...upstream...downstream...it's all the same. So Bavi is weakly immunogenic. Another unfortunate observation for us. Hopefully it will be weakly helpful immunologically too when they finally figure out the right application for Bavi. And I believe that sooner or later PPHM, or someone, will get it right.
zumantu: FAB. Absolutely fabulous. "We would like to pay tribute to the late Dr. Philip Thorpe (at UTSW, and PPHM). "We thank Peregrine Pharmaceuticals Inc., Tustin, CA, for the provision of PGN635 antibody." Truly another "turning point in the treatment of the devastating brain tumor glioblastoma multiforme, GBM. This is one of the factors that keeps me aboard here. Thank you for the reference. As I've posted here numerous times, Bavi for the tumor vasculature, and Cotara for the tumor center. That combination makes sense. When will it come to that? I curse the day PPHM had to choose chemotherapy to add Bavi to, and immune-oncology as a standard-bearer. I-O is mostly a hoax that makes no sense. Pursuing Bavi's affinity to blood vessels that feed cancer cells does make sense. Bali coupled with nanoparticles is sensible. Coupling Bavi with an agent like Cotara that penetrates to tumor center and kills core cancer cells makes all the sense in the world. Now we are getting somewhere.
Hey Sensex, very good post. Lotsa good stuff there. Appreciate your analysis. We've been invested about the same time, and we are both still here. That speaks volumes. Do not agree with your short list of the scientific savvy on this board. Some are faithful and well-informed, but actually only one scientist in your list, and none on that list with significant clinical or experimental experience. Peregrine has some very valuable tickets, and a huge amount of clinical experience now. They got to this point with an incredible run of good choices. Bali + chemo was not one of them. However, we've both been here long enough to know that, at the time, there was no choice. Aminophospholipid therapy is a natural,and it will happen. So is radioactive iodine. Immunological cure for advanced solid cancers remains a pipe dream. It simply is not going to happen.
jj, can you (or someone) give the full name and/or title of the publication? I missed it. thanks.
thanks ten. very informative article. eom
entdoc flashback post Monday, 07/19/10 11:34:05 PM #53989 Hard to believe this was 6 years ago:
"Here's the deal: PPHM's monoclonal antibody Bavituximab has been used now in combination with standard chemotherapy and found to "not interfere" in any way with results of chemo/cancer treatment, but probably actually improves results. PPHMs MAB Bavituximab now has an established safety profile. That is Huge! Huge, and that safety profile is for an inferior grade MAB [e.g. Bavituximab], one made up, in part, of mouse parts which may cause increased levels of allergic reaction. So Bavi may be safely added to standard chemotherapy. "Naked" [unarmed] Bavi was NEVER NEVER intended to be a stand-alone cancer killer. NEVER! But a lagniape that we never imagined is that BAvi is probably an immunological stimulant even when "unarmed" and used in the cancer treatment mix. And that immune boost is documented in severely immunologically crippled advanced cancer cases. But we are not, repeat NOT, in this because Bavi showed some measurable improved survival even unarmed. We, like BMY, are after the biggie: fully-armed a fully humanized MAB cancer bomb. That's the cancer killer. Not chemo. Not naked Bavi. Read my lips: it is fully armed and fully humanized Bavi. BMY has their full-humanized MAB that docks on anti-EGF. PPHM's MAB has a better, more universally applicable cancer docking site, -PS. The science is a done deal. The animal trials are finished. The theory is sound. The patents are there. The strategy is to add two known quantities together to fight cancer, fully-armed and fully human MAB Bavi. It's a no-brainer, that's where we're going. The coup de grace is to move fully armed and fully human Bavi directly into PIIB human trials. That's why we're here. That's when the PPS share kickstarts.
SK looked me in the eye three years ago and said, "I believe Bavi works". And I believed him. That is, I believed he was sincere in his belief. I did not believe unarmed, "naked" immunogenic Bavi was going to make a significant difference in the fight against solid cancer. If you remember, Bavi was originally a double-armed MAB missile which could carry a payload of cytotoxins in one hand, and attach to the "flipped" membrane -PS antigen with the other. But then reality (scientific reality) intervened in that scheme just as it did with Bavi as a better Avastin. I believed SK was sincere, and as a Bavi pioneer and insider that he had more information that I. That too was an item of faith. But I am a pretty good judge of men, and I think he was, and probably still is, sincerely a believer in Bavi... and that the recent PIII results must have been a crushing surprise to him.
However, having been a pioneering investigator in one of the seminal "discoveries" and new treatments of the last century, I saw firsthand how much its inventor believed during that discovery's debut...and how utterly unrealistic his beliefs were. That is the bad news. The good news is that even if that invention and this one, Bavi, did not turn out to be all the inventors believed them to be at the time, this one, Bavi, will be good enough for several applications...none of which will be solid cancers. As stockholders we have footed the bill to determine that this monoclonal antibody is safe, and (in my opinion) it is a good bet that Bavi or other similar anti-phospholipid antibodies will be found to be clinically applicable. PPHM has the inside track in this seminal area of inquiry, and we must encourage continued preeminence in the field.
djohn, it wouldn't surprise me if Bavi is a double or triple with anti-viral, although it has not panned out to date. The good news in this respect is that the company truly did try to buckle down and stay focused on their business plan from the onset of Garnick forward, subordinating most energy to the Bavi-Doce lung cancer trial. I am very interested in Bavi (or similar) for chronic inflammatory processes, and think that should be a focus...or even alzheimer's disease. At least we know it is safe (?). There is much more to come.
catboat, careful. Giving away Bavi and/or the antiphospholipid platform would be a horrible breach of contract with investors. It is still very early in the game believe it or not. If it were available I would take Bavi as a preventative, if not for therapy, but the key will be Bavi application early in the disease process. No way is Immune-Oncology going to prevail over large and metastatic solid tumors. The immunotherapy must have the head-start, not the tumor. It is going to take quite a while to prove this thesis though. This stock could make your grandchildren wealthy...and healthy?
aikifredicist: exactly! This approach, irradiation + Bavi,is the most sensible. I-O alone is not, for the most part, going to eradicate large solid tumors. Pretty soon the concept will catch on.
good economically based primer for ImmunoOncology (I-O): http://www.economist.com/news/science-and-technology/21653602-doctors-are-tryingwith-some-successto-recruit-immune-system-help.
The history of immune-oncology goes back to 1796, at least, and tumor immune-onclogy dates back at least 100 years.