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Maybe, but on the other hand, they started talking about combining blockade inhibitors with DCVax-Direct as part of the upcoming phase 2 some time ago.
I don't think you can tell for certain from what they said/wrote... but I have formulated my guess.
Each of the three cancers would be tackled in at least 3 different ways corresponding to 3 different adjunct checkpoint modulators provided by three different companies.
Would each of the three phase 2's also have a DCVax only leg? A nothing / control leg? Up to 5 legs per trial if they do. Mass parallel processing. The most cost effective way, the fastest way, and fairest way.
I think they are talking about DCVax-Direct. Could be working on something for L, but I think they are talking about Direct here.
Ohhh. Re Germans and TMZ. At screening it is too late to allow for any benefit seen by a difference in TMZ administration observed by the Germans when they took a peek at their L data to evaluate reimbursement for HE because some of those changes might be during SOC / prior to screening.
So... screening for DCVax-L might have been halted so that any future patients screened into the trial would come from a patient population with the tweeked TMZ/SOC prior to screening. This would expand the number of patients in this category to be observed for any subsequent approval consideration, and it would also be the right thing to do regarding patients... sort of.
Is that getting closer to your guess Flipper?
"Doktornolittle can probably fill you in". I think you are probably giving me undue credit as far as the detail of the recent findings go.
Way back I read about immune system damage from TMZ being a limiting factor in it's application. After reading that I have been trying to find out why they give TMZ to the unmethylated population, where I think it is known to either not help or not help very much. (perhaps it is or was not so easy to identify the unmethylated population soon enough). Particularly when being used in conjunction with an immunotherapy.
I guess I did push the idea that even within the methylated population, it is intuitive that the optimum dosage of TMZ when in use with DCVax-L would be lower than when being used on it's own. The optimum balance would almost certainly have to shift toward a lower dose. I say almost...
But the results of the Italian study are apparently a little more specific regarding when the application of TMZ should end. It is apparently not just the dose, but a detail on when it should and should not be applied. A detail in the study that you caught and I missed.
But I thought you might be talking to me Flipper, just wasn't sure of the answer. I suppose the Germans may have been ahead of the Italian group on this, and they may have stopped dosing sooner, in alignment with the results of that Italian study. Perhaps the Germans created their own study in their wing of the DCVax-L trial, inadvertently or not, with a larger patient population than the Italians, and with the same results. If so, the trial could have been halted at the point the Germans were looking at their data for HE reimbursement evaluation and concluded that their method is better... so all future patients should be getting their treatment. Or... making a little more sense, they saw what appeared to be better benefit with their limited TMZ regimen, and wanted to have a look at the rest of the data as verification. Or something like that. I am missing something here. Why did they need to halt the trial for this?
Based on the above considerations, if correct, and optimum might be to exclude TMZ for the unmethylated population and stop giving it before DCVax administration for the methylated population. Maybe that is what the Germans were already doing.
Feuerstein: Correction: You claim you are not giving investment advice, when clearly that is your job, and has been from the beginning when Cramer created you. But on a regular basis, you go further than just signaling your army of winged-monkey nitwits when to short in concert... you constantly give opinions on the technical / clinical side of things.
I realize you have an MD adviser from big Pharma, but that does not impress me. One guy's opinion, likely biased by his big Pharma perspective, then translated by a professional basher... not impressed on the clinical side.
Feuerstein: Your say you are giving investment advice, but the truth is you constantly give strong opinions on the clinical side of things. You do have some exceptional smarts in some areas, but your track record demonstrates that does not include the clinical side of things.
This board includes a large number of M.D.'s, Ph.D.'s and other highly skilled and intelligent people; scores of people with more knowledge and better judgement than you on the clinical side of things. Yet your influence is several orders of magnitude larger than these more qualified and honest individuals.
I am not saying that your lack of credentials ensures that you do not know what you are talking about. I am just saying that you do not know what you are talking about.
I didn't know that much detail of the violation was known. Sounds much less scary than it could be. How much over the 20% limit that you are talking about did they go?
Does your remedy jeopardize LP's majority shareholder/votes status?
If she does have a majority of shares as most believe, does that not relieve her from having to have such votes? Apparently not, but wanting to understand why not.
exwannabe said:
"The L P3 trial has gone lost for 9 months or so."
Glass half full or have empty. You guys have gone to town with this one. Sentiment expressed the other view very well today. Darkness is scary, but they are apparently not allowed to say much. 9 months without any info in a blinded P3... not so unusual. Stocks don't tank for that reason.
"The D P2 did not start. And now they are hyping I/O combos like every other failing small biotech is doing."
The SP tanked and financing dried up. Financing dried up in part because low oil prices have caused problems with fracking loans. A huge issue for the US Banks. Add Shrkeli's stunt that spurred a national attack on pharma... and really not a good time to fund a new trial. Desperate to ad CM/BI partners because no efficacy...? I'm not sure. I don't think so. I think they probably are seeing significant efficacy, but that is not good enough if fantastic efficacy could be had with a cocktail. Why waste time on good when fantastic might be available. Hodge's wife died. That is plenty of reason for me to want them to do better. First plan I heard was to have both a Direct only leg, and a Direct + CM/BI leg. If that changed to only with CM/BI then maybe you are right... but CM/BI + Direct leg is not a recent change-up. That was in the plans some time ago. Such partnerships take much longer than people expect. I followed another small-cap with similar plans and they were wayyyyyyyyy late also.
"L Lieu states the L P3 is no longer about L vs non-L, which makes it useless for approval."
That is not exactly what she said. She said both legs are living longer. She didn't say that the difference in the legs was less than expected. She didn't say progression was longer than expected in both legs. She doesn't know. AF twisted it, as you have done, and broadcast that version, signaling all his little men to drop their shorts... on the enemy, a therapy for brain cancer. Hard to know what the effect of LL's statement would have been without AF's army jumping on the issue.
"The only real significant investor has formally expressed concerns."
True, but in direct response to the Phase V article, according to the investor. An article with no listed authors or sources; written by shorts... the only thing that was revealed. And an investor previously famous for very aggressive takeover attempts. Cause for a 94% drop in SP???? I don't think so. All looks very fishy to any unbiased person.
"A few investors with access to the books launched lawsuits basically asserting the CEO is ripping them off"
I don't know enough about this to argue.
"The NASDAQ dinged them for improperly giving shares to the CEO's company."
I agree... possibly a big deal, but most of damage was done long before this recent issue. The NWBO / Cognate relationship bothered me for years until I had seen enough to understand that having an independent manufacturer would be a bad plan. Maybe better for the companies to be merged, but independent would be a mistake. I believe, the close tie and mutual LP control is proper / best situation. However, that invites very loose books and dubious dealings. LP apparently crossed the lines, but how badly? If the $ involved were not huge and the dealings not super slimy, then it doesn't matter much to me. But hard to know at this point. Misdeeds may be much smaller than many assume... or much larger. If larger, then we want part of Cognate, and over-site. If not... then LP makes good next catalyst which I believe is hoped for soon. May not happen, but I believe LP thinks such is likely and plans to deal with NAS after, when money is available and people aren't as pissed-off.
"The company has admitted to lax internal controls and is working to correct them."
What I care about is the big $. Lax internal controls don't concern me if they don't add up to a lot of money mishandled, which I realize they might. But that is to be seen. I don't think that admission caused a huge amount of money to flow out of $NWBO stocks. Maybe. Guys like Buffet look at those internals more than us retail fans of DCVax. So maybe, but again, that was pretty recent. Most of the damage to the SP was done long before that PR/SEC doc.
"brash, rude, posters here that handle themselves like common thugs"...
Maybe so; But as Sir Charles Barkley once said, "Every winning team needs at least one convict.".
Winning here means living long enough to see efficacy results for both L and Direct. If NWBO is really delaying such reveals due to poor efficacy, then you are right... but if they are honestly just trying to survive to see those results and to get all trial considerations to allow a fair evaluation for this new modality... then we are right to do what we are doing and to be emotional about it.
"Senti....u haven't been right all year on anything."
Sentiment is a highly motivated, very talented researcher and writer. You are saying that none of the clinicals she has dug up and posted have been right? She made them up?
To be blunt... she is a couple of levels above you, Turtle. You mostly just rant. She has contributed an enormous volume of good information, and if these immunotherapies ultimately prove out, she can rightfully claim to be one of the message board contributors that helped them see it through to the end.
I don't remember you ever posting anything relevant other than your feelings about the immediate situation Turtle. Not that such is not worth posting, it is, but Sentiment does a hll of a lot more than post her feelings.
Yes. To be sure it was a temporary truce. But dogs are so innocent and loving. They don't matter as much as people... but they matter a lot.
So if NWBO is in the crpr then why have LP and Les not sold any shares? IMUC execs sold shares for weeks before the bad news.
I think there might be a cherry bomb in the shorts.
"First there is a letter from the Nasdaq confirming de-listing then it could be postponed for at least a year."
I don't know how long they have to work out things with the NAS regarding the violation(s), but that wasn't what Dade or whatever his name was said was an imminent danger for de-listing. He said the SP and then exwannabe added market cap as imminent cause for de-listing when that just isn't the case; not even close to being true. That time scale is longer than the time scale for expecting some read on efficacy... bottom line.
Unless these NAS violation(s) cannot be resolved, efficacy will control the future... unless you guys manage to strangle the company. Efficacy, which is a big unknown, but no bigger than it was 10 months ago when the stock was over $12.
Sorry about your dog AF. I had you blocked, so did not know you had posted when I added a dig in my last post. Edited out some of it in respect for your loss.
About a year ago I was present for putting down a dog that I had walked for many years. Belonged to a friend with a bad back.
I had walked a pair of dogs. One died of cancer, then 6 months later this second one was simply dying of old age.
While at the vet, in the final moments, I started to leave the room to get something for the owner, and he (the dog) got up and shut the door so I could not get out. He was scared. The feeling of his head suddenly growing very heavy in my hands is something I will never forget. My condolences.
"Reverse Split or delisting to OTC coming"
I think there is good reason to believe that some sort of efficacy feedback is likely, long before the NAS delists them for SP or market cap deficiency. I think it is 6 months that you have to be underwater to get the second notice, to which most companies respond with a request for extension, and it is usually granted.
So... in citing SP and market cap as eminent reasons for delist, you are misleading people. But that is your game, isn't it? So you, and out-of-nowhere "Dade", and others like you have helped to drive the SP to the point that a year from now, if it doesn't recover, they could delist... and then you point at the issue, a week or so after the year countdown starts, and say it is imminent. I'm putting you on ignore. Your game is transparent.
DCVax-L may not get approval and may not get reimbursement for the German Hospital Exemption... but that is an understood risk in literally every single smallcap biotech. The reasons provide by Pyrrho that this trial will fail are totally countered by the positive study results posted by RK. The ridiculous argument that fighting cancer is analogous to hunting elephants, and that therefore using an enormous quantity of a single antigen, rather than literally every mutant antigen in the tumor as with DCVax-L was shot down completely by the amature posters on this board.
This will come down to efficacy. You will not beat LP in your attempted funding quash.
The pending NAS violations could be enough to bring the company down... we don't know. No details provided or apparently required to be provided. But you and whoever thl "Dade" is, didn't even mention that... because it was not your long term agenda. Driving to this low PPS and then prematurely talking about de-listing was your agenda but you are both too stupid to change gears.
Thanks. (That is why I still call it "Temador" or "TMZ").
I am not a big believer in hanging someone because they had motive for a crime... but if you are looking for people with motive to prevent DCVax-L from succeeding, you might include the insurance companies.
I think that if there is price manipulation, the insurance companies are more likely behind it than BP. BP may have a fundamental character inconsistent with such slimery. Big investors in BP... that could be a different story.
Hedge funds heavily invested in oncology focused BP's... and insurance companies. And of course NW who has been known to be very aggressive in taking over companies. These people have motive. Doesn't make them guilty... but they have motive.
"After the report comes out, I hope there will be a counter-suit. Fiduciary responsibility by fund managers is viewed differently in the UK than it is here."
This recent supreme court decision that such suits can be pursued at the state level is apparently a big deal. I wonder a little if some actions have been awaiting that decision. Of course I am a hopeful long. The appearance of AF on this board the day after that decision does not align with my hope here.
It appears likely, to me, that the internal investigation did dig up some improper dealings with cognate, leading to the alleged (and almost certainly true) NAS charges of violations. No way to know how large or serious those violations were at this point.
But if those violations are all there is to air, then LP is no longer in the position of having to submit to abuse by outsiders who may effectively have the goods on her. So both the airing of dirty laundry and the supreme court decision may align to allow the lawsuit on NWBO's behalf that you talk about. Something impossible, or at least pointless, only a week ago.
"Below is a very helpful abstract. Also note, NWBO's GBM trial will also consider adjuvant temalazoid usage in their final covariate analysis -- according to the old protocol."
I could read the article a few more times and get more out of it, but what I think I read is that the timing of TMZ administration may be critical to long term patient survival due to a negative effect on immune memory formation as currently administered, or at least as administered for these experiments.
I would like to read the article to say... that TMZ is bad in conjunction with DC therapy for GBM. But whether the article says that or not, I believe there is strong evidence to the contrary. So instead, I interpret the findings as; while TMZ is beneficial (maybe only to methylated patient group, but that is large) it could be a lot more beneficial if we can find the correct dosing and timing coordination with DC administration to avoid stunting the formation of immune memory cells. On the other hand, this is additional evidence that maybe TMZ should not be administered to the unmethylated patient population. (you may recall my harping on this question for years now Flipper).
A BFDeal!!!! This study is another big insite into the details of what is going on in DCVax therapies. Another giant step forward, potentially.
Ever spend a lot of time trying to find a lost screw or key or something in a dark space that you can barely reach.. maybe with coat hanger or something... and no luck. Ie fishing a wire across studs inside a wall... Then you finally get a tiny flashlight and contort yourself to actually get a peak into the void... and a minute later you are done.
Added knowledge like this is golden. Kudos to the people doing that work. I hope that such knowledge can be put to work after the fact in trials like NW's trials. So much is learned these days in the length of a trial... they may have to come up with new policies to accommodate that fact.
Immunotherapies are nacient compared to chemotherapies... so they should not be judged upon current efficacy alone. Findings like this will improve the efficacy for immunotherapies continually for decades, whether it be Celldex's or IMUC's or AGEN's or NWBO's. I think that should be a consideration in approvals.
"Is abstract 3092 proof of concept for d.cells and pdl1 inhibitors?"
Looks that way. There are only 7 patients, and only 2 responders... but apparently they would expect no responders with past therapies including the blockade inhibitor alone. They don't exactly say that, however.
If I take the attitude that these guys know a lot more than me, so weigh their conclusion heavily, then yes... it appears this is evidence that DC Vaccines and Blockade Inhibitors may indeed be synergistic and very importantly, may lower the amount of BI needed for efficacy, resulting in lower side effects. That would be the hope, and that is their conclusion.
"Here we show that systemic anti-PD-1 therapy for patients with pancreatic cancer can be effective even at lower dose when combined with DC vaccine therapy."
Elsewhere they say the side effects were not bad.
There are others that you should ask here. RK, Flipper, maybe Pyrhho, etc, and the real doctors, Reefrad, Highwayman, etc... Of course you already know Pyrrho's answer.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858628/
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World J Gastroenterol. 2016 May 14; 22(18): 4446–4458.
Published online 2016 May 14. doi: 10.3748/wjg.v22.i18.4446
PMCID: PMC4858628
Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer
Mikio Kajihara, Kazuki Takakura, Tomoya Kanai, Zensho Ito, Yoshihiro Matsumoto, Shigetaka Shimodaira, Masato Okamoto, Toshifumi Ohkusa, and Shigeo Koido
Author information ? Article notes ? Copyright and License information ?
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Abstract
The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients.
Keywords: Pancreatic cancer, Dendritic cell, Whole tumor cell, Cancer vaccine, Cytotoxic T lymphocyte
Core tip: Chemotherapy and cell-based cancer vaccines such as dendritic cell- and whole tumor cell-based cancer vaccines can synergize to result in increased efficacies in patients with pancreatic ductal adenocarcinoma (PDA). Moreover, cell-based cancer vaccines and immune checkpoint inhibitors can be used to block inhibitory ligand/receptor interactions by acting on certain cancer cells or T cells, allowing an enhancement of the antitumor immune response in specific tumors, including PDA. Therefore, the blockade of immune regulatory checkpoints combined with cell-based cancer vaccines and/or chemotherapy may be effective in inducing adaptive antitumor immunity in patients with PDA.
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INTRODUCTION
Pancreatic ductal adenocarcinoma (PDA), which is derived from glandular tissue of the pancreas, accounts for approximately 95% of pancreatic cancer and is one of the most lethal cancers because of a propensity for metastatic spread[1,2]. Although the definitive treatment for early-stage PDA is surgical resection, this is only possible in approximately 15% of cases[3], as most patients with PDA present in an advanced stage at the time of diagnosis. Additionally, despite surgical resection, radiation and/or chemotherapy, patients with PDA have an overall 5-year survival of only 5% due to local recurrence and metastasis[1,2,4]. PDA cells grow rapidly and spread outside of the pancreas, including into the liver, lung, bone, and brain, through lymphatic and/or blood vessels. The current standard chemotherapy for patients with advanced PDA is gemcitabine. Gemcitabine can also be combined with nab-paclitaxel[5] or erlotinib[6], resulting in improved survival. Moreover, a multi-chemotherapy regimen (FOLFIRINOX) consisting of 5-fluorouracil, folinic acid, oxaliplatin and irinotecan has been associated with significant improvement in survival for patients with advanced PDA[7]. However, the currently used chemotherapeutic agents have still failed to demonstrate satisfactory clinical advantages in patients with advanced PDA. It has been well demonstrated that PDA is relatively resistant to chemotherapy, so new therapeutic strategies are urgently needed to improve pancreatic cancer treatment. Regarding potential targets for cancer vaccines, PDA cells express numerous tumor-associated antigens (TAAs), such as Wilms’ tumor gene 1 (WT1)[8], mucin 1 (MUC1)[9], human telomerase reverse transcriptase (hTERT)[10], mutated K-Ras[11], survivin[12], carcinoembryonic antigen (CEA)[13], epidermal growth factor receptor 2 (HER-2)[14], and p53[15]. Therefore, cancer vaccines targeting these TAAs may be an alternative approach for treating patients with PDA.
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INDUCTION OF ANTITUMOR IMMUNE RESPONSES
Cancer cells degrade endogenous antigens into short peptides (usually 8-10 amino acids) and present them via major histocompatibility complex (MHC) class I molecules. These cells express numerous TAA-derived peptides on their cell surface as a result of malignant transformation. Meanwhile, T cells with the aß T cell receptor (TCR) express CD4+ T cell or CD8+ T cell lineage markers[16]. Interaction of the TCR on CD8+ cytotoxic T lymphocytes (CTLs) with the complexes of antigenic peptides and MHC class I molecules on tumor cells is a critical event in the T cell-mediated antitumor immune response. However, induction of CD8+ CTLs also requires antigenic peptides to be presented on the surface of antigen-presenting cells (APCs) in the context of MHC class I molecules. It has become clear that dendritic cells (DCs) are the most potent APCs in the human body and play a pivotal role in the initiation, programming, and regulation of antitumor immune responses[17]. DCs can process endogenously synthesized antigens into peptides, which are presented on the cell surface as peptide/MHC class I complexes, but require activation signals to differentiate and eventually migrate to the regional lymph nodes, where they are recognized by the aß TCR on CD8+ T cells[17]. Moreover, DCs capture and process exogenous antigens and present peptide/MHC class I complexes through an endogenous pathway via a process known as antigen cross-presentation[18]. This cross-presentation is essential for the initiation of CD8+ CTL responses[19]. In contrast, exogenous antigens from the extracellular environment are captured and delivered to the compartments of the endosome/lysosome, where they are degraded into antigenic peptides, which are then complexed with MHC class II and recognized by the aß TCR of CD4+ T cells[17]. Finally, mature DCs can present TAAs to naive CD4+ and CD8+ T cells in the regional lymph nodes; these T cells then differentiate into activated T cells. It is well known that in the induction of efficient CD8+ CTL responses against cancer cells, CD4+ T cells are essential for the priming of CD8+ CTLs through activation of APCs and production of interleukin (IL)-2 and interferon (IFN)-?[20]. CD4+ T cells also play an important role in the maintenance and infiltration of CD8+ CTLs at a tumor site[21]. Therefore, activation of antigen-specific CD4+ and CD8+ T cell responses by cell-based cancer vaccines, such as either DCs loaded with TAAs or modified whole tumor cells, is essential to induce efficient antitumor immunity against pancreatic cancer cells[22].
PDA cells can evade immune control through several mechanisms. One major mechanism is the immunosuppressive tumor microenvironment. The microenvironment in pancreatic cancer in particular consists of PDA cells and stroma cells, such as cancer-associated fibroblasts (CAFs), tolerogenic DCs, myeloid-derived suppressor cells (MDSCs), immunosuppressive tumor-associated macrophages (TAMs), and regulatory T cells (Tregs). Importantly, PDA cells themselves induce immune suppression through production of immunosuppressive substances such as cytokines [e.g., transforming growth factor (TGF)-ß, IL-10, and IL-6, vascular endothelial growth factor (VEGF), Fas ligand (Fas-L), programmed cell death-1 (PD-1) ligand (PD-L1) and indoleamine-2, and 3-dioxygenase (IDO)][22,23]. These immunosuppressive cells inhibit antitumor immunity by various mechanisms, including depletion of arginine and elaboration of reactive oxygen species (ROS) and nitrogen oxide (NO)[22,23]. The pancreatic cancer microenvironment not only contributes to pancreatic cancer-induced immune suppression but also might be closely related to the extent of disease. For example, T cells producing IL-22 were significantly increased in PDA tissue, and this increase was significantly associated with tumor staging and poor prognosis[24]. Moreover, Tregs, MDSCs, and T helper 17 (Th17) cells in intratumoral tissue elicited strong immune suppression in patients[25,26]. As a result, CD8+ CTL function in patients with advanced PDA is impaired by IL-10 and TGF-ß from Tregs. Therefore, DC-based cancer vaccines against PDA cells that cause induction of TAA-specific CD4+ and CD8+ T cells combined with depletion of immunosuppressive cells may tip the balance in favor of immunostimulation.
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DC-BSAED CANCER VACCINES
The aim of cancer vaccines is to induce efficient antitumor immunity. Peptide vaccines are frequently used because they are simple, safe, and economical. However, certain obstacles prevent the use of peptide vaccines from becoming widespread. The drawbacks of peptide vaccines are related to numerous factors: (1) the limited number of known synthesized short peptides cannot be presented via many MHC molecules[27]; (2) monoclonal CD8+ CTLs may be ineffective in reacting to PDA cells[28]; (3) certain TAAs and MHC class I molecules are occasionally down-regulated, which may occur during tumor progression[28]; and (4) DCs may have impaired function in patients with advanced PDA[29]. Therefore, in vitro-generated mature DCs have been developed as cancer vaccines because of their powerful ability to induce antigen-specific CD4+ T cells and CD8+ CTL responses in preclinical and clinical studies[30]. To date, the majority of DC-based cancer vaccines have been generated using monocyte-derived DCs. Immature DCs can be generated by a single leukapheresis after culture in the presence of granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-4. In our laboratory, immature DCs are activated for vaccines by incubation with penicillin-killed and lyophilized preparations of a low-virulence strain (Su) of Streptococcus pyogenes (OK-432) and with prostaglandin E2 (PGE2), after which a large number of DCs can be cryopreserved in ready-for-use aliquots[31]. Several strategies have been used to develop DC-based cancer vaccines to elicit efficient antitumor immune responses (Table ?(Table1).1). To induce DC presentation of TAAs, DCs have been loaded with TAAs in the form of tumor lysates[32], antigenic peptides[33], dying or dead tumor cells[34], mRNA[35,36], cDNA[37], or exosomes[38] or have been fused with whole tumor cells to form hybrid cells[39]. The strategy of fusing DCs and whole tumor cells is based on the facts that DCs are potent APCs and that whole tumor cells express abundant TAAs, including both known and unidentified TAAs[40-42]. Therefore, DC-tumor fusion cells can process a broad array of TAAs and present them via MHC class I and class II in the context of co-stimulatory molecules[40-42]. Moreover, many adjuvants, including Toll-like receptor (TLR)3, TLR9, synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG, polyinosinic:polycytidylic acid (polyI:C), IL-2, IL-12, and IL-18, have been used in DC-based cancer vaccines to maximize antitumor immune responses in preclinical studies[43].
Table 1
Table 1
Cell-based cancer vaccines
The field of cancer vaccines for PDA is currently in an active state of clinical investigation. In particular, the development of DC-based cancer treatments is of great importance. Clinical trials of DC-based cancer vaccines for PDA patients have been conducted (Table ?(Table2),2), including clinical trials for an MUC1-targeted DC-based cancer vaccination regimen. MUC1 is a TAA consisting of a polymorphic, glycosylated type I transmembrane protein present in glandular epithelium and overexpressed in 90% of PDAs. Importantly, MUC1 is associated with poor prognosis, enhanced metastasis and chemoresistance[9,44]. It has been reported MUC1-targeted cancer vaccines were effective in inducing antitumor immunity in murine pancreatic cancer models[45]. Therefore, several groups have conducted clinical trials with DCs loaded with MUC1 peptide (DCs/MUC1 peptide) or transfected with MUC1 cDNA (DCs/MUC1 cDNA). In a phase I/II clinical trial, following surgical resection, 12 patients with pancreatic or biliary cancer were vaccinated with MUC1 peptide-loaded DCs. These patients were followed for more than 4 years after vaccination, at which point 4 were alive and without recurrence[46]. In another phase I study of 16 patients with PDA who were vaccinated with DCs/MUC1 peptide, 2 of 15 patients with resected PDA were alive and disease free at 32 or 61 mo[47]. Moreover, 7 PDA patients were vaccinated with DCs/MUC1 peptide in a phase I trial[48]; these patients showed MUC1-specific immune responses, although there was no significant clinical benefit. MUC1-specific immune responses were also observed in 4 of 10 PDA patients following vaccination with DCs/MUC1 cDNA in a phase I/II trial[49]. Although the MUC1-targeted DC-based cancer vaccination regimen was safe and a significant MUC1-specific immune response was observed in several enrolled PDA patients, further investigation is warranted.
Table 2
Table 2
Clinical trials of dendritic cell-based cancer vaccines in pancreatic cancer patients
WT1
The WT1 antigen is also one of the most widely expressed TAAs in various tumor types, including PDA[50,51]. Importantly, WT1 has been ranked by the National Cancer Institute (NCI) as the number 1 target for cancer vaccines based on several factors: (1) therapeutic function; (2) immunogenicity; (3) the role of the antigen in oncogenicity; (4) specificity; (5) the expression level and percentage of antigen-positive cells; (6) stem cell expression; (7) the number of patients with antigen-positive cancers; (8) the number of antigenic epitopes; and (9) the cellular location of antigen expression[52]. WT1 has been found to be oncogenic, rather than tumor suppressive, in tumorigenesis[53]. Moreover, both cellular and humoral immune responses against the WT1 protein are naturally elicited in cancer patients, indicating that the WT1 gene product is highly immunogenic[54,55]. Therefore, we and other groups have been performing clinical trials of the efficacy of WT1-targeted cancer vaccines for patients with PDA[31,56-63]. Four clinical reports about the use of DCs loaded with WT1 peptides combined with standard chemotherapy, such as gemcitabine, to treat advanced PDA patients have been published[31,56,60,61]. The vaccines can be mainly classified into 2 groups: (1) DCs loaded with MHC class I-restricted WT1 peptides (DC/WT1-I)[56,60,61] and (2) DCs loaded with multiple MHC class I- and class II-restricted WT1 peptides (DC/WT1-I/II)[31]. Both DC/WT1-I and DC/WT1-I/II vaccinations are associated with significant induction of WT1-specific CD8+ T cells in circulating blood. In one study, Kobayashi et al[60] analyzed 255 PDA patients who received standard chemotherapy combined with DC-based cancer vaccines, including DC/WT1-I. The median survival time (MST) from diagnosis was 16.5 mo. Interestingly, an erythema reaction at the vaccination site was a prognostic factor for a significant survival benefit. DC/WT1-I-based cancer vaccines alone or combined with lymphokine-activated killer (LAK) cells were also retrospectively analyzed in 49 PDA patients[56]. Among all 49 patients, 2 had complete remission, 5 had a partial response, and 10 had stable disease. The survival of patients receiving DC-based cancer vaccines and standard chemotherapy (gemcitabine and/or S-1, an oral fluoropyridine) plus LAK cells was significantly longer than the survival of those receiving the vaccine in combination with chemotherapy but no LAK cells. Moreover, a prospective clinical trial using DC/WT1-I combined with gemcitabine demonstrated that the therapy was feasible, tolerable and effective in PDA patients without liver metastases[61]. We also conducted a phase I study of chemoimmunotherapy using DC/WT1-I/II vaccines and standard chemotherapy (gemcitabine and/or S-1) in 7 advanced PDA patients[31,57,62]. The combination therapy was well tolerated, and WT1-specific IFN-?-producing CD4+ and CD8+ T cells were significantly increased following treatment with DC/WT1-I/II. WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of the 7 patients with PDA who were vaccinated with DC/WT1-I/II and in 0 of the 3 patients with PDA who were vaccinated with DC/WT1-I or DCs loaded with MHC class II-restricted WT1 peptides (DC/WT1-II). Moreover, the MST and the median progression-free survival (PFS) of the patients with PDA who were vaccinated with DC/WT1-I/II were significantly longer than the MST and PFS of those receiving the DC/WT1-I or DC/WT1-II vaccine. In addition, the WT1-specific DTH-positive patients who received DC/WT1-I/II showed significantly improved overall survival (OS) and PFS compared with the negative-control patients. In particular, all 3 PDA patients with strong WT1-specific DTH reactions had a median OS of 717 d. Surprisingly, a patient with multiple liver metastases remained alive for more than 1000 d and received more than 71 vaccinations; this patient had strong WT1-specific DTH reactions throughout the vaccination period[63]. The combination of DC/WT1-I/II and chemotherapy induced long-term WT1-specific CD4+ and CD8+ T cell responses. DC/WT1-I/II may elicit not only effector but also long-lived effector memory and central memory T cells, all of which are capable of recognizing WT1-positive PDA cells and which are therefore associated with long-term stable disease[57].
hTERT
hTERT, the catalytic subunit of a functional telomerase complex, is also widely expressed in most human tumors and plays an essential role in tumor progression[64]. Therapeutic strategies targeting such antigens involved in tumor growth resulted in antitumor immune responses in a mouse study[65]. As loss of telomerase activity may inhibit the progression of PDA cells, hTERT is a widely applicable target for triggering CTL responses. It was demonstrated that hTERT-specific immune responses were safely induced in a PDA patient vaccinated with DCs transfected with hTERT mRNA (DCs/hTERT mRNA)[66]. In this clinical study, DCs/hTERT mRNA vaccination was specifically administered to a PDA patient with relapsed disease[67]. The patient could not receive chemotherapy due to severe neutropenia and thus was vaccinated with DCs/hTERT mRNA alone for 3 years, which resulted in no evidence of active disease. The vaccinated patient also showed induction of strong immune responses to multiple hTERT epitopes. Therefore, hTERT-targeted DC-based cancer vaccines may be an effective approach for treating patients with PDA.
CEA
PDA cells widely express CEA, a glycosylated protein, so induction of CEA-specific immune responses may be associated with survival benefits[67]. In one clinical trial, 3 patients with resected PDA received neoadjuvant therapy, including DCs loaded with CEA mRNA (DCs/CEA mRNA), for 6 mo[68]. In this trial, all 3 PDA patients showed injection site reactivity and remained alive and without recurrence at more than 2.5 years from the original diagnosis. Although CEA-targeted cancer vaccinations induce strong CEA-specific immune responses, they usually fail to eradicate the tumor in most patients with advanced disease[67]. The results may be at least partly associated with the immunosuppressive effects of the tumor microenvironment. Therefore, to improve the clinical efficacy of CEA-targeted cancer vaccines, we need to design improved strategies that can overcome the immunosuppressive tumor microenvironment.
KRAS
As the KRAS gene is mutated in up to 95% of PDA cells[69], targeting mutant K-ras-specific immune responses may influence the clinical benefits of treatment for PDA patients[70]. To induce K-ras-specific antitumor immunity, irradiated peripheral blood mononuclear cells (PBMCs) were used as APCs and loaded with a K-ras epitope[71]. In this clinical trial, 9 patients with PDA, all with KRAS mutations, were vaccinated. Only one patient showed a positive cellular immune response, resulting in a median OS of 60 d. The worse prognosis of PDA patients subjected to an immunization protocol using PBMCs as APCs may be associated with impaired induction of antitumor immune responses per se. The vaccination protocol could be improved using mature DCs instead of PBMCs.
DCs combination therapy
The major cytokines currently in use or under evaluation for use in cancer vaccines are IFN-a, IL-2, GM-CSF, and IL-12[72]. An alternative strategy for clinical trials of DC-based cancer vaccines is use of IL-12-secreting DCs[73]. The main source of IL-12 in humans is DCs, and IL-12 acts as a major orchestrator of the T helper 1 (Th1)-type immune response against cancer when present directly in the tumor[74]. Therefore, 3 PDA patients were vaccinated with DCs transfected with an adenovirus encoding the IL-12 gene (DCs/IL-12)[73]. The intratumoral DC injections were mainly guided by ultrasound. DCs/IL-12 induced significantly increased infiltration of CD8+ T cells in certain patients, and a partial response was observed in 1 of the 3 patients with PDA[73]. As the DCs were not loaded with TAAs, cross-presentation of TAAs by the DCs in the patients must have been induced by IL-12. Another group reported administering gemcitabine and an endoscopic ultrasound-guided fine-needle injection of OK432-activated DCs into tumors in 5 PDA patients, followed by intravenous infusion of CD3-stimulated LAK cells[75]. Three of the 5 patients demonstrated effective responses: 1 had a partial response, and 2 had long-term stable disease for more than 6 mo[75]. The median OS was 478 d in this phase I trial. In the patient with partial remission, induction of tumor antigen-specific CTLs was observed.
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WHOLE TUMOR CELL-BASED CANCER VACCINES
Whole tumor cells can be genetically modified to produce cytokines to enhance antitumor responses. A GM-CSF-secreting, irradiated, allogeneic PDA cell line (GVAX) has been investigated in multiple phase I and II studies[76-82] (Table ?(Table3).3). GVAX recruits and activates DCs and promotes presentation of TAAs by DCs for activation of CD4+ and CD8+ T cells[83,84]. Early clinical trials demonstrated that vaccination with GVAX enhances CD8+ CTL responses against multiple mesothelin-specific epitopes that have been correlated with survival benefits[76-78]. As cancer vaccines alone have usually failed to demonstrate significant clinical activity in advanced PDA patients, PDAs are considered as non-immunogenic tumors, which is due to the immunosuppressive tumor microenvironment[80]. Recently, 39 PDA patients received GVAX alone or in combination with low-dose cyclophosphamide (Cy) to deplete Tregs[80]. Importantly, 33 of the 39 patients treated with GVAX showed the formation of vaccine-induced lymphoid aggregates. Moreover, the post-GVAX CTL infiltration and aggregate formation resulted in up-regulation of immunosuppressive regulatory mechanisms, including the PD-1/PD-L1 pathway. Therefore, GVAX-vaccinated PDA patients are better candidates for immune checkpoint therapies than vaccine-naive patients[79]. In a mouse study, a GVAX vaccine combined with anti-PD-1 antibody blockade improved murine survival compared with anti-PD-1 antibody or GVAX alone[85]. In a clinical trial, although GVAX alone also failed to show clinical benefits in PDA patients, infiltration of activated T cells expressing CTL-associated antigen 4 (CTLA-4) and PD-1 was induced by GVAX[80]. The efficiency of immune checkpoint-targeting agents is dependent on induction of adaptive immune responses[86]. Thus, they conducted combination therapy with inhibition of the CTLA-4 pathway using ipilimumab (anti-CTLA-4) and GVAX in metastatic PDA patients[79]. Three of 15 patients had evidence of prolonged disease stabilization (31, 71, or 81 wk), and 7 patients experienced a decline in carbohydrate antigen 19-9 (CA19-9). In 2 of these patients, disease stabilization occurred after an initial period of progression. The median OS was 5.7 mo, and 1-year OS was 27%. Among patients with OS > 4.3 mo, there was an increase in the peak mesothelin-specific T cell count and enhancement of the T cell repertoire[79]. Moreover, immunosuppressive pathways in the tumor microenvironment were overcome by the addition of the GVAX vaccine and low-dose Cy for PD-1 blockade. Therefore, combining anti-PD-1 or anti-PD-L1 antibody therapy with cancer vaccines such as GVAX may be effective therapy for PDA patients. In addition, they demonstrated that GVAX coupled with low-dose Cy followed by treatment with CRS-207 (live-attenuated Listeria monocytogenes expressing mesothelin) induced innate and adaptive immunity in 61 PDA patients. Mesothelin-specific CD8+ CTL responses enhanced by GVAX/Cy/CRS-207 were associated with longer OS (n = 61, 9.7 mo) compared with the responses enhanced by GVAX/Cy (n = 29, 4.6 mo)[81].
Table 3
Table 3
Clinical trials of whole tumor cell-based cancer vaccines in pancreatic cancer patients
Whole tumor cells can be genetically modified to produce cytokines to inhibit tumor cell production of immunosuppressive cytokines, such as TGF-ß, IL-10, IL-6, and VEGF. In particular, TGF-ß has a critical role in immunosuppressive mechanisms, so down-regulation of TGF-ß activates DCs and increases TAA-specific CTL induction. In mouse studies, several strategies to inhibit the production of TGF-ß by cancer cells were developed. For example, TGF-ß production by cancer cells was inhibited by the administration of neutralizing antibodies[87,88] and small interfering RNAs (siRNAs)[89] or constructs coding for a soluble variant of the TGF-ß receptor[90]. We have previously demonstrated that the production of TGF-ß, IL-10 and VEGF by human PDA cells is significantly limited upon exposure to pharmaceutical-grade ethanol, without decreased expression of MHC class I and MUC1[91]. Therefore, whole tumor cells genetically modified to express immunosuppressive cytokines, such as GM-CSF, and to inhibit immunosuppressive cytokines, such as TGF-ß, are better candidates for the generation of DC-based cancer vaccines for PDA patients.
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CELL-BASED CANCER VACCINES COMBINED WITH CHEMOTHERAPY
Cytotoxic chemotherapy has been known to blunt immune responses because of the toxic effects of these treatments on dividing bone marrow progenitor cells, including lymphocytes. However, increasing evidence has suggested that cancer vaccines have the possibility of achieving better effects if combined with chemotherapy[92]. Cancer cells undergoing immunogenic apoptosis due to chemotherapy express calreticulin (CRT), which is a Ca2+-binding chaperone on the cell surface that mediates efficient phagocytosis by DCs[93,94]. In addition, high-mobility group box 1 (HMGB1)[95,96] and pentraxin-3 (PTX3)[97] are released from late-stage dying cancer cells to activate DCs and modulate immune responses via a TLR4-dependent signaling pathway. Therefore, necrotic or apoptotic tumor cells induced by chemotherapeutic agents enhance immunogenicity and can be effectively taken up by DCs, resulting in efficient processing of TAAs for presentation to T cells. For example, a standard cytotoxic agent for PDA, gemcitabine, can enhance the cross-presentation of TAAs by DCs as well as CTL induction[98]. Moreover, Cy and gemcitabine can each augment the antitumor effects by depleting immunosuppressive cells such as Tregs, B cells and MDSCs as well as by inducing the proliferation of DCs, all of which potentially enhances the antitumor immune response[98-101]. We also reported that up-regulated presentation of WT1 peptide via MHC class I molecules on PDA cells is induced by exposure of the cells to gemcitabine and/or S-1[102]. Importantly, WT1-specific CTLs can more efficiently lyse gemcitabine-treated PDA cells than untreated cells[102]. Certain TAAs that are not usually expressed on cancer cells may be uncovered by treating cancer cells with chemotherapeutic agents; these antigens are good targets for cancer vaccines because they can be effectively recognized by antigen-specific CTLs[103]. Therefore, cancer vaccines can synergize with chemotherapy in targeting PDA cells[104]. In addition, our recent reports indicate that the combination of gemcitabine and trastuzumab conjugated to a cytotoxic agent (T-DM1) may be a promising modality for the treatment of PDA cells with low human epidermal growth factor 2 (HER2) expression as a result of the unique HER2-up-regulating effect of gemcitabine[105]. Importantly, cancer patients who have previously received cancer vaccines could also benefit more from subsequent chemotherapy than those patients who are not vaccinated[106].
Although conventional treatments such as chemotherapy can eradicate certain cancer cells, the remaining cancer stem cells (CSCs) can lead to tumor relapse. Although CSCs have been implicated in chemoresistance, these remaining CSCs are still attractive targets for cancer vaccines[107,108]. Therefore, it is desirable to develop a novel therapy that selectively targets CSCs via cancer vaccines, which can be combined with conventional chemotherapy. Indeed, expression of TAAs such as MUC1 is up-regulated in CSCs by chemotherapy, and CSCs are efficiently lysed by MUC1-specific CTLs[108,109]. CSC-loaded DC-based cancer vaccines may be an alternative approach. We have reported that DCs fused with CSC cells induced CSC-specific CD4+ and CD8+ T cells with high production of IFN-?, which is predominantly produced by Th1 cells[108]. Therefore, developing surgery/chemotherapy targeting the bulk of cancer cells combined with cell-based cancer vaccines targeting CSCs is highly desirable.
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CONCLUSION
CTLA-4 and PD-1 are well-described co-inhibitory molecules that are highly expressed by TAAs-specific CTLs and associated with impaired antitumor immune responses. In contrast, PD-L1, which binds to PD-1, is not constitutively expressed in tumor cells but is induced in response to IFN-? produced by activated T cells[110]. Therefore, immune checkpoint inhibitors, such as CTLA-4, PD-1 and anti-PD-L1 antibody, may be an efficient means for treating cancer patients[110]. Indeed, antibodies can be used to block inhibitory ligand/receptor interactions by acting on certain cancer cells (e.g., anti-PD-L1) or T cells (e.g., anti-CTLA-4 or anti-PD-1), allowing enhancement of the antitumor immune response in specific tumors[111]. However, single-agent immune checkpoint inhibitors, such as CTLA-4, PD-1, and anti-PD-L1 antibody, elicit limited adaptive immune responses in PDA patients due to the non-immunogenic tumor microenvironment, which provides a formidable barrier to CTL infiltration at baseline[85]. Therefore, cell-based cancer vaccines may prime PDA patients for treatment with better candidate checkpoint inhibitors[112]. Combining a blockade of multiple inhibitory pathways with cell-based cancer vaccines may synergistically decrease T cell anergy and improve clinical benefits.
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Footnotes
Conflict-of-interest statement: The authors declare no conflicts of interest regarding this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Peer-review started: January 16, 2016
First decision: March 21, 2016
Article in press: April 15, 2016
P- Reviewer: Amedei A, Kleeff J S- Editor: Gong ZM L- Editor: A E- Editor: Ma S
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"Is abstract 3092 proof of concept for d.cells and pdl1 inhibitors?"
Do you have a link to the abstract? I saw reference to it posted on yhoo a while ago, but I have not found the abstract in google searches. I will try the ASCO website but if you have a link please provide it.
They gave stats for the new mutation under study, but not for methylation or the overlap, which was the eventual focus of the article. That is a big deal though. Great article! Progress. Any new knowledge is progress and could lead to better therapies directly or indirectly.
How about them Warriors! They are playing again tonight! A very important game because they lost their first home game in the playoff series with Oklahoma.
Did you hear a sliding trombone in the background? Sliding slowly in then slowly out...?
Good point that GBM would not be the only market for L and inoperable would not be the only market for Direct.
I don't remember the model that inspired the Direct = 10X L estimate.
While L could be applicable to all operable solid tumor cancers, the leanings of the long posters, at one point, was that if Direct proves out, it will likely replace L for most situations with GBM and prostate being likely exceptions. Direct is cheaper and easier than L (and it already has automated mfg). But tumor burden issues began to weigh heavy in the opinions / guesses at some point so that many believe that Direct will likely not replace L for these many operable situations.
Of course all this could be moot...
...but if they are continuing with the development of automation for L, and the efficacy proves descent, then maybe it will see the huge market you are talking about for operable tumors. That of course would be much much larger than $2B, $3B, or $5B.
Some real valuation numbers: A very formal NPV report was released about a year or two ago for a large number of current drugs/treatments in trials. There were probably 50 such drugs in the report. They gave an estimated NPV of $5B for DCVax-L on approval.
I think that is an over-estimate if they were approved for the entire population with an increase in PFS of only 4 months. I know the Germans fund medical procedures based on efficacy. I believe they do the same in the UK, and I suspect the US (insurance companies, medicare, etc) policies, statistically, are similar.
Further, if only a subgroup were to get approved, one would think that would reduce the NPV proportionally, possibly offset by high efficacy shown for that subgroup.
Then there is the current environment regarding drug pricing. Nobody wants to brag about a high price for their drug. So...
Maybe $2B + some increase in credibility of DCVax-Direct which most think has a much larger market than DCVax-L. So... $3B dependin...?
Currently that would be about $30/share, but if the trial drags out to the point that they are diluted 100%, then that would be $15. Those are the broad numbers I might expect with many additional $ if DCVax Direct begins to prove out.
Many think that DCVax-Direct is worth 10X DCVax-L if it proves out. I can't support that number, but it is the one I have had in my head for a couple of years.
I believe that is where the $300 number came from. It was an estimate of $30/sh for L if approved and an order of magnitude more for Direct.
Exactly. Hindsight is a powerful investment tool. The ultimate!
Just eliminating patients with severely damaged immune systems should improve stats for DCVax-L. Actually it should improve the control group performance also... Well, at least observing such stats should create pressure to be more careful with SOC to not damage the immune system.
Patients are living longer. That appears to be a fact. I think the DCVax-L trial was a big part of bringing that about, whether or not it ultimately shows efficacy. That is somewhat of a win for the altruistic here, regardless of the success of the company.
"by Reefrad that Lymphocyte count was added to the trial as a covariate"
Lymphocyte count in the tumors or some lymphocyte count in the blood? It would be nice if it was the blood, assuming that is was a good predictor in the blood. Much better if you can identify the candidate before surgery.
"Here's the quick and easy--if you wanted to even just do that with ITT and all four subtypes, each subtype would need around 300 patients. The DCVax-L study would be at least 1,200 patients, or thereabouts."
That would be to reach statistical significance with the same straight efficacy threshold for the subgroup that was set for the larger population, ie months OS or months PFS. What I said was that if the efficacy is high enough for the subgroup (ie much higher than the bar set) then you could reach statistical significance with a small subgroup. The efficacy weighs in beyond just reaching or not reaching the bar originally set for approval for the entire patient population.
I'm not talking about FDA policy, I am talking about the definition of statistical significance.
Not rational Pyrrho. Both examples that you link point to analysis of results for subgroups that were not specified apriori. In my post I acknowledged that creating a subgroup after the fact is a problem, and point to methylation status which was setup as a covariant apriori.
I go on to yield that I don't know if announcing a covariant is the same as announcing subgroup... . Do you know?
I think the cashless warrants that AEZS contracted were a scam, not simply a desperation move to finance. There is a difference.
NWBO could ultimately prove to have been a scam, but at this point I don't believe that is the case. I believe they really couldn't get other financing recently, or that possibly there was some deal made to offset some wrong doing on NWBO's part. That could be called a scam, but there is an issue of proportion here. Even if the warrants had been given away for free, what was the dilution? I'm not certain to be honest, but if it was about 6.6M shares then that was less than 7% dilution vs 1000% for AEZS, or was it 10,000%. Either way... AEZS'd dilution was 2 or 3 orders of magnitude more dilution than NWBO's recent dilution... Not belonging in the same conversation.
"Adam is correct no matter what happens in the P3."
You think that demonstrated efficacy will have no bearing on the survival of this company? Of course you don't. Your not a moron Pyrrho. So... what are you here for saying these ridiculous things?
Pyrrho must want some cheap calls. They move by 5 cent increments... Those are often huge percentages, depending on which calls. He probably wants the July calls, which are currently at about 15 cents... or last sold at about 15 cents but the ask is way up... probably at 45 cents. He probably hopes to shake some down to 10 cents.
The purpose of the German HE is to provide to patients promising drugs that are not yet statistically proven out but are convincing enough in efficacy. It also provides sustaining revenue to companies with trials that show promising results but are not yet at statistical significance.
Mesenchymal is a very large subgroup. Further, statistical significance is not just determined by trial size or group size, it is also determined by efficacy. If there is very good efficacy in that large subgroup then I would think it could reach statistical significance with the current planned trial size, and possibly even the current enrollment.
If mesenchymal was not specified as a subgroup before a look at the data, however, I would think that would be a problem, based on the things AVII has brought up and linked to. The trial docs that Reefrad recently posted list methylation status as a covariant, but do not mention mesenchymal. I don't know the difference between listing something as a subgroup vs a covariant. Reefrad did not discuss it.
There is great skepticism by AVII (and probably RK and yourself) regarding the patients in the long survival tail of the phase 1. If you guys are wrong, however, and if those patients are representative of the results that will be seen in the phase 3, then it appears that about half of the mesenchymals will have very long survival. One has to wonder if that (about) half is the methylated (about) half.
If so, then methylation status might be nearly as good a predictor of long term survival as mesenchymal. Again, methylation status was listed as a covariant for the trial.
It is hard not to like Cramer. That is unfortunate. What is more unfortunate is the following:
In his infamous videotape he describes illegal tactics used by hedge funds to get out of bad short positions. The tactics are manipulation of investors through dissemination of false information. He goes on to say that you need access to high profile people at CNBC in order to accomplish this manipulation.
It seems clear to me that in the videotape Cramer is talking about his former hedge fund. He was co-owner of a hedge fund, then either quit or was fired, depending on who's story you believe, and went on to create "The Street". Then came his other shows on CNBC. In the video he appears to be sort of telling on his former hedge fund... who I believe fired him. A disgruntled former owner.
So, instead of going behind bars for apparently admitting to the regular practice of highly illegal maneuvers involving orders of magnitude more money than Martha Stewart went to prison for... he ends up with a show on CNBC... the exact position he describes in the video as needed to accomplish the illegal manipulation that he described.
Unbelievable. Absolute crooks running this country. A system that allows virtually anything to be done to retail investors, for instance.
More exactly, it seems ludicrous to trust that Cramer would not eventually regain below board ties with that former hedge fund or with former investors at another hedge fund... and use his position to accomplish the crimes that he described.
But you and others have made it sound like it (AEZS' situation) has happened here. Important to note that it has not.
German HE reimbursement at some solid level would not be as big a catalyst as an approval by the FDA or EMA... but it would be big.
German HE reimbursement at a low level might be perceived negative... and that could be looming. It would fit much of what we have seen recently. But if that happens, scrutinize the deal. With the trial incomplete, are they only funding for the low end of the variance, rather than the mean? Is there potential future adjustment in reimbursement as the trial matures and the variance drops? Is Northwest going to finish the trial... hard to tell true intent from a head-fake... but if such an HE read comes, we will understand the silence; that it was necessary. And if we understand the silence, maybe some trust can return. (And if we find out what the NAS infraction was.).
"When a financing transaction is so hard to follow that you can't follow it, that's a pretty reliable sell signal, IMO:"
I agree, sort of... but I have seen agreements much more confusing. I don't know if you followed AEZS's infamous "cashless warrant exercise" which drove their death spiral, but that agreement was easily an order of magnitude more confusing than this one, deliberately so, and it was designed to fk retail on a large scale. Literally 90% of retail shares were handed to the institutional investors by the deal. I don't even know if those institutional investors had preferred shares... if they did, what need for the smoke and mirrors?
NWBO's deal was not a death spiral deal in the same sense. Not even close. They may be in a de-facto death spiral, but it is not an engineered death spiral. I have seen one. There is a big difference.
This deal is scary because it suggests strongly that NWBO does not have have good news coming any time soon, or worse, that they are sinking their own ship.
On the other hand...
This will make Pyrrho puke, but I have to look for feasible positive explanations.
I am all in, but I don't have all that much to lose to be honest. And I have followed the company and stock for 3 years. So I want to be here for whatever is about to happen... even if that is collapse, or continuation of a slow bleed, and silence. (I used to own 24K shares, but that was 3 years ago, and my loss of the vast majority of those shares was not the doing of NWBO or LP.)
The fact is we are at the end of both a legal inquiry and possibly an efficacy read. The legal inquiry was to satisfy a very big fish who had dumped an enormous sum into the company. Maybe NW is the one getting the $1 warrants/shares to compensate for what he (and or his investors) feel(s) was over-payment and also to help him not take NWBO to court over whatever dirt they dug up. Many think NW cannot buy now due to an NDA/Insider restrictions, and some insider information. Maybe that is not the case.
Or... this could similarly be negotiations with some other party, for similar reasons.
And so, maybe they are just tying up all these loose ends before the big news Wednesday, or June 4, or any day now unrelated to ASCO! You see, there is nothing that cannot be rationalized if you try hard enough!
You just have to believe Pyrrhonian!
Is this the publication that you are referencing Flipper? I think these two guys are from Kings College, and it does contain the statement about subgroups. But... still the details of when the subgroups were defined is of interest.
Maybe they were defined from the beginning, but just not discussed because it shows lack of confidence about approval for the entire patient population. But somewhere along the line I was left believing that they added subgroups, so I will keep looking. But for now time to go to work.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4514134/
The PR that I remembered having new statements about subgroups (which it doesn't) was Aug 11, 2014. Maybe if someone kept better notes than I did they might find such new statements by LP around that time. I do believe it was around that time that discussion of subgroups entered the conversation, but maybe the subgroups were defined prior, but never discussed prior.
I suppose the new screening criterion of having an intact immune system could be called a subgroup for post analysis, if the needed lab tests were done in the past prior to entry in the trial. But that is not the type of subgroup I thought had been referenced, and they way I remember it, LP talked about multiple subgroups.
http://www.nwbio.com/nw-bio-obtains-approvals-for-enhancements-of-phase-iii-trial-of-dcvax-l-for-gbm-brain-cancer/
Your right Reefrad. I just dug up the PR I thought mentioned the addition of subgroups, and there is no such statement. Maybe it was a webcast at about that time... Do you remember when they added the subgroups? From the beginning? I thought not.