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For the record,
Apparently IHUB removed my recent critiques --
"Reason -- Off Topic"
No problem.
Afford said:
then MS Powrs I thought said the financials never looked better ( debt wise) I believe and then this which some say they were expecting like Flip.
Afford, I think that NWBO is fully in German/European manufacturing Expansion Mode. They are also opening 30 clinics in a very short time. AF could be right that it is Height Capital, but it is still a good sign regarding expansion and future revenue prospects. I think Austin is right about the outstanding share issue, but Long can correct me if I'm wrong, I think we are at more like 100-105 million outstanding if all outstanding warrant and options were exercised.
He usually posts this stuff on Seeking Alpha as well. Anyway, if he leaves it subscription only, I think it's mostly proprietary, but he does see the financing as a positive indicator for future European revenue prospects -- that's partly in the title.
Larry Smith has a new article on the financing. Unlike recent reports, he seems to be tempering expectations for Direct at ASCO.
In case you'd like to know what I mean by "tempering."
1. To modify by the addition of a moderating element; moderate: "temper its doctrinaire logic with a little practical wisdom" (Robert H. Jackson). -- Free Dictionary by Farflex
The interviewer seemed very nervous. Maybe an off day for him, I can empathize if that was the case; but the show did not reflect the status NWBO's progress should demand at this point -- it seemed lightweight. I think they can do better. Maybe Terry Gross on PBS, if Terry hasn't retired. (Must admit I don't listen to talk shows much anymore unless one pops up during due diligence research.)
Anyway, thanks Hodge!
Best Wishes to your family through this difficult time.
Ns!
Good to know you and yours are well.
-- Flip
Have a good day.
DCVAX-Direct does not likely take "months" to start achieving tumor reduction, "my man." If DCVAX-Direct is as good as some people think, it will, in time, be used far more than L. L would be used where surgery is imminently necessary in a matter of days to a couple of weeks. However, since you refer to my position as "absurd" and "covert," I'll quit rambling on while cloaked in a veil of secrecy.
Casual Observation:
Someone probably already mentioned this.
The international manufacturing approvals, German (and forthcoming Great Britain) hospital exemptions, clinic trainings and openings (the forthcoming European expansion will take us past 80 clinics of excellence globally), the very mature compassionate use program in Israel, price negotiations with DCVAX-L, all bring me to the conclusion that incorporating DCVAX-Direct into every one of these systems will be far easier and streamlined because DCVAX-L did all the heavy lifting -- so to speak.
It's an obvious casual observation, which we've always intuitively known, but probably worth mentioning again.
Afford,
Anything is possible, but the evidence is becoming quite compelling toward these agents for all three programs. Please look at the very informative and digestible article written by Marnix Bosch and company in 2003, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC239912/ , and trace that into NWBO's October 2012 patent application, http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=17&f=G&l=50&co1=AND&d=PG01&s1=northwest&s2=biotherapeutics&OS=northwest+AND+biotherapeutics&RS=northwest+AND+biotherapeutics ,and compare that with the 2008 10K
recently referenced, followed by the 2013 PATENT awarded regarding "Generation of dendritic cells from monocytic dendritic precursor cells with GM-CSF in the absence of additional cytokines," http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=1&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=6&f=G&l=50&co1=AND&d=PTXT&s1=northwest&s2=biotherapeutics&OS=northwest+AND+biotherapeutics&RS=northwest+AND+biotherapeutics.
My last reply to your post did not come out right. I really meant to say I appreciate your historical context, and I hope I'm not confused when I think that NWBO improved upon the old practice. I think BCG never enters the body with direct. Instead, BCG, is "double-dead," to use Dok's phrase, prior to maturing the dendritic cell. Moreover, none of the BCG, other than its antigens/biomarkers -- through DC uptake -- are placed into the tumor and/or human body. I think.
(We already know through 3 separate vaccines in various trials this appears incredibly safe.)
Yes, I found an old 10K from 2008.
It's probably in other documents, but the 2008 10k was handy.
The DCs used in the formulation of DCVax®-Direct are activated through a process similar to that used for DCVax®-Brain and DCVax®-Prostate (i.e. using heat-killed and formalin-fixed BCG mycobacteria and interferon gamma), although they are not loaded with tumor antigens prior to injection.
The use of BCG in the Direct, L and Prostate trial appears to be one step removed from the ways BCG was used historically in TB and bladder cancer. I hope others could save me another trip into the stacks on this one. I'm pretty certain I understand the different methodology and protocol, but I think it's worth discussing the new (and better?) way NWBO appears to be utilizing it.
Did you notice Haiku is the correct spelling for a form of Japanese verse, but Hiku means tail (noun) in Japanese:)
How about a Tuesday Hiku to end the afternoon?
Think Long tail my friend.
I.M.U.C. waits for one.
Northwest wags their tail.
MolBiol, I agree with you in that the paper is not written in a manner that can be readily deciphered by a ham-and-egger like me, or even an expert such as yourself, without needing to speculate far too much. I think the conclusions by Bosch on the Triozzi paper, combined with the injected lesions, non-injected lesions and control lesions injected with lidocaine, in the Triozzi study, leads to many possible interpretations. (No interpretations seem cataclysmic)
What I find helpful is that I firmly believe Triozzi and Bosch spoke about it at some point. I also think there is no doubt Bosch solved many of the issues we are discussing today over the past ten years -- Examples: best matrix, best maturing agents, best maturation state, best migration facilitation, best avoidance of down regulation, etc.
I hope you'll look at the last few posts I wrote speculating upon the likely injection "matrix" and Dendritic cell maturation agents.
Thanks.
Dok, ….and here is my guess for the DC maturation agents that were used in the secret sauce.
Dendritic Cells partially matured by exposure to heat killed and formalin fixed BCG (5.times.10.sup.6 cfu/ml) IFN.gamma. (500 U/ml). -- Patent Application
Dok, so here is my guess for causing aptosis of some tumor cells while not harming the Dendritic Cells.
(For others, please see prior posts to see how we could be having this conversation).
What might be in the syringe?
Time release nanoencapsualtion of the 'dendritic cells and maturation agents' surrounded by a liquid "matrix" environment of Hydrogen Peroxide.
The hydrogen peroxide would work quickly to immediately kill and slowly kill a number of tumor cells. The micro encapsulated dendritic cell and maturation mixture soon thereafter are released into the "dead zone" -- now devoid of hydrogen peroxide (which converts into water).
Sounds like science-fiction, but the patent makes it plausible, and time release micro-encapsualtion technology makes it feasible. I think UCLA might be one of the leading universities in time release nano-encapsulation.
I think your question is the next logical inquiry.
I think this might be one clue (aka: a temporary barrier protecting the dendritic cell)
As above, the cells can be formulated in a slow release matrix. When administered in this fashion, the formulation can be administered by a means appropriate for the matrix used. Other methods and modes of administration applicable to the present invention are well known to the skilled artisan. -- patent application
Fair enough. Very good information. So there could naturally be a cache, if you will, of dead and dying cancer cells in certain cancers. This would provide yet another source. All the better.
Dok, I think you are onto something here!
Dok said:
The secret sauce might well be what causes the….inflammation*.
Upon injection, the DCs take up antigen from apoptotic or dying tumor cells, and present the antigen to T cells after migration to the lymph nodes. -- Marnix Bosch
Once the partially mature dendritic cells have matured within the tumor as measured by the production of, for example, TNF-.alpha. and IL-12, and the expression of the chemokine receptor CCR7, the cells can migrate to the lymph nodes where the cells will contact T cells to up regulate the immune response to the tumor antigens. -- Patent Application
POWERS LINDA F Officer 12/12/2012 Buy indirect 6,468,153 10,809,992
Read more: http://www.nasdaq.com/symbol/nwbo/insider-trades#ixzz2yJOvHFKa
Forgot to cite the source.
United States Patent Application
Bosch; Marnix L. October 4, 2012
(just a month or 2 before LP made a dramatic personal investment into this company)
Examples of DCVAX-Direct Efficacy in humans and mice.
Example 1
[0042] In the present example, monocytic dendritic cell precursors, isolated by tangential flow filtration, were cultured at a concentration of 10.sup.6 monocytes/ml in X-VIVO 15.RTM. supplemented with 2% human serum albumin (HSA) and 500 U/ml of GM-CSF in either flasks or cell bags. After 5 days, the DCs from the flasks and the bags were either left untreated (iDCs) or were partially matured for 4 hours in the presence of BCG (1:400 dilution) and interferon .gamma. (IFN.gamma., 500 U/ml)(pmDCs). The cells were collected, washed and mixed with an equal number of fluorescently labeled irradiated PKH67-A549 tumor cells for 48 hours. Following the incubation, the cells were washed, stained with a phycoerythrin (PE) labeled monoclonal antibody specific for CD11c, and analyzed by flow cytometry. The values provided in Table I represent the percentage of CD11c.sup.+ cells within the DC gate that were also positive for labeled PKI-167 antigen (MFI=mean fluorescent intensity). Controls included DCs mixed with PKH67-A549 cells just prior to analysis.
TABLE-US-00001 TABLE 1 Treatment % CD11c.sup.+PKH67.sup.+ Cells MFI iDCs-flask 87.6 235.2 pmDCs-flask 90.7 610.2 iDCs-bag 72.8 403.5 pmDCs-bag 91.3 557.5
[0043] These data demonstrate that the partially matured DCs were better at antigen uptake in this assay than immature dendritic cells, as measured by either the percentage of cells that take up antigen or by the amount of material picked up by the tumor cells.
[0044] In another example, a leukapheresis was carried out on a human patient subsequent to surgery for removal of a tumor growth. Monocytes were purified from the leukapheresis product by tangential flow filtration. The purified monocytes were differentiated as described above and partially matured by exposure to heat killed and formalin fixed BCG (5.times.10.sup.6 cfu/ml) IFN.gamma. (500 U/ml). The partially matured dendritic cells were formulated for administration and injected into the tumor bed of the individual, under ultrasound guidance. Dendritic cells isolated from the individual were found to be capable of inducing a tumor specific cytotoxic T cell response when measured in vitro. Further, it was found that the time to tumor recurrence was prevented or substantially delayed.
Example 2
[0045] In this example human colon cancer cells were grafted into mice to form tumor xenografts by well known methods. After the tumors were established, animals were divided into groups and the animals of each group were administered either placebo, immature dendritic cells or partially matured dendritic cells into the tumor. The size of the tumor was subsequently measured and compared for each group.
[0046] Briefly, human CT26 colon carcinoma tumors were established in female Balb/c mice by injecting 100,000 tumor cells in the right flank under the skin. Treatment was initiated on day 15, at which time all mice had palpable tumors with tumor sizes ranging between 10 mm.sup.2 and 45 mm.sup.2.
[0047] Dendritic cells were prepared from the femoral bone marrow of female Balb/c mice following standard protocols. Briefly, bone marrow cells following red cell lysis were incubated with murine GM-CSF (200 U/ml) and IL-4 (200 U/ml) in RPMI 1640 supplemented with 10% fetal bovine serum for 13-14 days, with addition of fresh media with cytokines after 3 and 7 days. To obtain partially matured dendritic cells, the cells were exposed to a 400-fold dilution of inactivated Bacillus Calmette-Guerin (BCG) that had activity of 0.5-1.times.10.sup.6 colony forming units per milliliter prior to inactivation, and to 500 units of murine interferon gamma (IFN.gamma.) per milliliter. The cells were incubated for 8 hours and then layered over 14.5% metrizamide and centrifuged for 15 minutes at 4.degree. C. and 1750 rpm. The interface was collected and the cells were washed and viably frozen in 10% dimethyl sulfoxide (DMSO) in liquid nitrogen storage. Following thawing at 37.degree. C., the cells were washed twice and resuspended at a concentration of 1 million cells per 50 microliters.
[0048] The tumor bearing mice were treated with cyclophosphamide (50 mg/kg) intraperitoneally on day 15 and 17. Dendritic cell injection in the tumor (either mock injection of 50 .mu.l of phosphate buffered saline, immature DC or DC matured for 8 hours) was performed on days 16, 17, 18 and 21). Tumor growth was measured every other day for 60 days.
[0049] In the group treated intratumorally with phosphate buffered saline, all 4 mice had tumors greater than 100 mm.sup.2 on or before day 40. In contrast, the mice treated intratumorally with immature DC had reduced tumor growth and 2 of 4 mice had tumors smaller than 100 mm.sup.2 on day 40. Three of the 4 mice treated with partially matured DC had tumors smaller than 100 mm.sup.2 on day 40, and two of those animals had no palpable tumors on day 50.
Example 3
[0050] In this example human colon cancer cells were injected into mice to from tumor xenografts by well known methods. Subsequent to the first injection of tumor cells the animals were administered a second dose of tumor cells. After 15 days, animals were divided into groups and the animals of each group were administered either placebo, immature dendritic cells or partially matured dendritic cells into the tumor. The size of the tumor was subsequently measured and compared for each group.
[0051] Briefly, human CT26 colon carcinoma tumors were established in female Balb/c mice by injecting 100,000 tumor cells in the right flank under the skin, followed by injection of 100,000 tumor cells in the left flank on day 3. Treatment was initiated on day 15, at which time all mice had palpable right-flank tumors with tumor sizes ranging between 10 mm.sup.2 and 45 mm.sup.2.
[0052] Dendritic cells were prepared from the femoral bone marrow of female Balb/c mice following standard protocols. Briefly, bone marrow cells following red cell lysis were incubated with murine GM-CSF (200 U/ml) and IL-4 (200 U/ml) in RPMI 1640 supplemented with 10% fetal bovine serum for 13-14 days, with addition of fresh media with cytokines after 3 and 7 days. To obtain partially matured dendritic cells, the cells were exposed to a 400-fold dilution of inactivated Bacillus Calmette-Guerin (BCG) that had activity of 0.5-1.times.10.sup.6 colony forming units per milliliter prior to inactivation, and to 500 units of murine interferon gamma per milliliter. The cells were then layered over 14.5% metrizamide and centrifuged for 15 minutes at 4.degree. C. and 1750 rpm. The interface was collected and the cells were washed and viably frozen in 10% dimethyl sulfoxide (DMSO) in liquid nitrogen storage. Following thawing at 37.degree. C., the cells were washed twice and resuspended at a concentration of 1 million cells per 50 microliters.
[0053] The tumor bearing mice were treated with cyclophosphamide (50 mg/kg) intraperitoneally on day 15 and 17. Dendritic cell injection in the right flank tumor (either mock injection of 50 .mu.l of phosphate buffered saline, immature DC, DC matured for 8 hours or DC matured for 24 hours was performed on days 16, 17, 18 and 21). Tumor growth was measured every other day for 60 days.
[0054] In the group treated intratumorally with phosphate buffered saline, all 5 mice had right-flank tumors greater than 100 mm.sup.2 before day 35, and 3/5 animals had left-flank tumors >100 mm.sup.2 on or before day 40. In contrast, the mice treated intratumorally (right side only) with immature DC had reduced tumor growth: one mouse had no palpable tumor on either side at day 60, and 4 of 5 mice had tumors <100 mm.sup.2 on both sides at day 40. Three of the 5 mice treated with 8 hour partially matured DC had completely resolved both tumors by day 50. In the group treated with DC that had been partially matured for 24 hours, tumor growth was reduced even further. Three of 5 mice completely resolved the tumors on both sides by day 50, one animal completely resolved the left-flank tumor, and partially controlled the right-flank tumor (<100 mm.sup.2 on day 40) and one animal partially controlled both tumors (<50 mm.sup.2 on both sides at day 40).
Example 4
[0055] In this example, human tumor cells were used to form xenograph tumors in mice as described above. The differentiated immature dendritic cells were partially matured by exposing the cells to the dendritic cell maturation agent imidazoquinoline R898 or R898 combined with BCG and IFN.gamma.. The partially matured dendritic cells, immature dendritic cells and a placebo were administered into the tumor and the size of the tumors in each group were compared.
[0056] Briefly, tumors were established in mice as in example 2. Dendritic cells were prepared as in examples 2 and 3, but partial maturation of the cells was achieved by exposing the cells to 5 .mu.g/ml of the immune response modifier (dendritic cell maturation agent) R848, or 5 .mu.g/ml of the immune response modifier R848 together with BCG and interferon gamma at the concentrations as set forth in examples 2 and 3, for 8 hours.
[0057] The treatment schedule was identical to example 3. None of the mice injected intratumorally with phosphate buffered saline controlled tumor growth. One of five mice treated with DC partially matured with R848 alone fully resolved tumor growth, as did 3 of 5 mice treated intratumorally with DC partially matured with R848 with BCG and IFN.gamma.. Nine mice from examples 3 and 4 that had completely resolved their tumors were challenged approximately 30 days after tumor resolution in the right flank with 1 million tumor cells. None of the animals showed detectable tumor growth demonstrating immunological protection against the CT26 tumor cells.
Example 5
[0058] In this example the dendritic cells prepared in the examples above were characterized for the expression of surface molecules. Briefly, murine dendritic cells, prepared as in experiments 2-4, were characterized for expression of cell surface molecules after staining with fluorescent antibodies and flow cytometric analysis. The results are presented as the percentage of cells positive for the phenotypic surface markers and the mean fluorescence intensity for certain surface markers in Tables 2 and 3.
TABLE-US-00002 TABLE 2 Percent positive cells treatment CD11c MHC-II CD80 CD86 CD54 CD40 Immature 66.9 68.1 62.2 28.1 62.6 1.4 R848 (8 hrs) 60.7 76.4 73.4 31.3 96.6 1.5 BCG/IFN (8 hrs) 59.5 85.5 84.9 66.0 96.0 2.0 BCG/IFN/R848 (8 hrs) 58.4 88.8 82.4 61.8 96.6 2.6 BCG/IFN (24 hrs) 66.3 91.5 90.0 84.4 95.3 3.3
TABLE-US-00003 TABLE 3 Mean fluorescence intensity treatment MHC-II CD80 CD86 CD54 CD40 Immature 395.7 50.0 30.7 53.8 3.0 R848 (8 hrs) 515.5 54.7 30.0 90.0 8.0 BCG/IFN (8 hrs) 751.1 79.1 74.6 120.3 7.2 BCG/IFN/R848 (8 hrs) 757.8 79.3 66.4 132.9 13.9 BCG/IFN (24 hrs) 876.8 97.9 99.0 126.9 11.4
Example 7
[0059] A [human] patient diagnosed with a solid tumor is treated with chemotherapy, radiation therapy, cryotherapy, or brachytherapy and subsequently with partially matured dendritic cells administered intratumorally. Following treatment, the tumor is resolved and the patient is protected from tumor recurrence.
[0060] The previous examples are provided to illustrate, but not to limit, the scope of the claimed inventions. Other variants of the inventions will be readily apparent to those of ordinary skill in the art and encompassed by the appended claims. All publications, patents, patent applications and other references cited herein and are also incorporated by reference herein in their entirety.
MolBiol, Post #8297 continued. [see also posts: 8293, 8275, 8256, 8241, 8212, 8133]
A. You said:
But once in the tumor the [dendritic] cells didn’t migrate. In fact, they probably de-differentiated due to the fact that CD86 (one of those necessary co-stimulatory molecules) was down-regulated. -- MolBiol
You must have meant something else here. Of course the dendritic cells migrate. They migrate back to the nearest lymph node. -- flipper
No, I said what I meant. The dendritic cells migrating to lymph tissue was the desired outcome, but was not what happened in the Triozzi et al. study. -- molbio
I thoroughly respectfully disagree with your final contention that all dendritic action requires a pro-inflammatory response to express in such a way as to properly activate the t-cell. Inflammatory response in the phagocytized invader is only one of many separate and unique ways dendritic cells are primed to properly express to the t-cells in the local lymph. -- flipper
I’m surprised to see you write this. Why exactly do you think the dendritic cells for Direct are exposed to agonists of Toll-like receptors (agents like BCG, interferon gamma and polyI:C)? It’s the pro-inflammatory cascade that leads to the presence of those all-important co-stimulatory molecules on the surface of immature DCs. By what mechanism do you propose activating the innate immune response? -- molbiol
In addition to their role in antigen presentation, dendritic cells also directly communicate with non-lymph tissue and survey non-lymph tissue for an injury signal (e.g., ischemia, infection, or inflammation) or tumor growth. Once signaled, dendritic cells initiate an immune response by releasing cytokines that stimulate activity of lymphocytes and monocytes. -- Marnix Bosch
I know you want to think it's an open question, but based upon my memory, and what alleged protocol document we confronted a few months ago -- that disappeared into thin air -- the pseudo progression group is that very cohort, and it was to be composed of 72 patients -- more if needed.
BTW, I had some board chats with Doclogic about these 4 other subgroups you mentioned. Very interesting. 240 +72 = 312.
Mol, it would be helpful in the future if you named the quotes as it could be misconstrued that some were mine that were not, and others were someone else's and were instead mine.
1. You said
With regard to the systemic response vs. systemic immunity, although one doesn’t always equal the other, in most cases I would say they do.
A complete response by one tumor or a partial response by another tumor is not a complete systemic response. There was absolutely no evidence whatsoever that there was a systemic response immune or otherwise in any of the patients.
Regressions of noninjected tumors were observed in two patients. One patient (Patient 8) with melanoma manifested a complete response of the injected tumor and eight other 0.5–1.0 cm satellite lesions within a 6-cm radius of the injected tumor. Another patient with breast carcinoma (Patient 6) manifested a minor regression, i.e., a 25% reduction in the sum of the products of the longest perpendicular dimensions of the injected tumor and of a noninjected tumor that was located within 5 cm of the injected tumor. There was no clinical evidence of systemic antitumor activity in metastatic lung or liver tumors present in the patients enrolled.
I agree with the idea of a split -- Eg. The DMC recommends a halt on the primary group and a continue with the pseudo progression group if the data allows.
However, I think ethicicists might rightfully just demand a halt on everything if one is halted. Therefore, I think what could be happening, it's just my opinion folks, is that the compromise might be to hold up the entire trial while some more events occur in the pseudo progression group -- maturation. The big question would then be, once they subject the pseudo progression group to the first interim "look," if the data is not mature enough to start showing separation, and the trial is split, how can enrollment continue for the pseudo progression group? This is not easy stuff by any means.
In other words, who wants to be the last patient to take a placebo in the DCVAX-L trial?
Pyrr,
They added the additional cohort (pseudo progression group) on May 2012 to expand the application for L. See the P.R.. To the best of my recollection, the unconfirmed document that passed this board's way some time ago, and then went into the ether, confirmed that the trial design was to then separately analyze the pseudo progression cohort once the primary group demonstrated statistically significant efficacy. Then the pseudo progression group stats, while a tertiary endpoint, would also be calculated as a whole with the primary group, but not for the purpose of establishing the primary endpoint. (But you would need enough data points from the pseudo progression group to do this, and since they started in May 2012, they may need to substantially enlarge their group to speed things up. In other words, the group needs to mature before it would start to show statistical separation. This can be done with time and/or by enlarging the group. Remember, the primary group did it with time and size, and they are a very mature cohort.)
(Interestingly, Ou recently pointed out there is precedent with the FDA in a similar sense, where the FDA changed the primary threshold for a subgroup. While i am not contending at all that this is being done here, I am contending that the pseudo progression group is far more important subgroup than many believe.)
While there is a chance you could be right that they are waiting for the secondary endpoint, which is overall survival in the primary group, I respectfully disagree. Besides, this would mean a continue, not a delay. IMHO, I suggest the long tail effect already established very significant efficacy in the primary treatment group OS.
MolBiol,
I'll address your comments, but for other readers, please note that while I distinguish between systemic general response and systemic immunity response below, to attempt to clear up Mol Bio's concerns; the point is, the Triozzi study culminated in 10 years of research to create DCVAX-Direct, which in Maurine studies, demonstrated full systemic tumor response and full systemic immunity in 80% to 100% of tumors -- injected and non injected throughout the body.
Now onto your substance.
1. First of all I did not contend this at all, as you claimed I did.
"THE DENDRITIC CELLS" "MIGRATE TO ANY OTHER LYMPH NODE TO GET A SYSTEMIC EFFECT."
So basically you wasted your breath because you did not read what I stated more clearly, because I found this did not happen. I only stated it was the question I was asked, upon which I set out to investigate.
2. You stated,
"The response described in the Triozzi et al. study was not a systemic response. Why do you present it as such? The authors themselves state very clearly in the text that: -- MolBiol
“Finally, although antitumor activity and antitumor-HSP lymphocytes were observed in situ, there was little clinical evidence to show that systemic antitumor immunity was elicited with IT DC therapy as it was applied….
“So Marnix Bosch and colleagues had to mature dendritic cells to the right stage so that when they were injected into tumorous cancer cells, the partially matured dendritic cells were predisposed to think whatever they encountered in the tumor was not normal.” -- Flipper
Dendritic cells have no way to determine if the antigen they are taking up and presenting is normal or not normal. Dendritic cells take up self and non-self (beneficial) antigens all the time. It’s just that in those circumstances there are no pro-inflammatory signals present that induce co-stimulatory molecules to be expressed and that are necessary to generate an immune response against the antigen that would include T and B cells. -- Molbiol
But once in the tumor the [dendritic] cells didn’t migrate. In fact, they probably de-differentiated due to the fact that CD86 (one of those necessary co-stimulatory molecules) was down-regulated. MolBiol
I think that even small biotech's do follow some trends in the biotech sector when break-out news is not readily apparent. For instance, (despite my contempt for Cramer after seeing his boasting/confessional video placed here originally by Diamondjim), he points out that the normal trend on a down biotech day is that the market will typically beat up more on those that have been doing well lately, whereas it will normally knock the recent laggards a little less aggressively. I have found this to be true to a degree, although there are always exceptions for no apparent reasons. It seems to work in reverse as well, on an up day, without any seemingly relevant news on a biotech company, the large and small stocks that were recently beaten down perform better than the stocks that have not taken a recent major hit. Again, there are always exceptions. Anyway, because I do not trade frequently, I'm just a casual observer observer. I also note that the small biotech's can and sometimes do follow chart patterns, but these patterns are so easily played by deep pockets (as Jim Cramer bragged about), that the exceptions to chart pattern analysis can also be very unpredictable.
MDAnderson's recent Temador Trial.
I know I've said this before, but I believe the delay relates to the pseudo-progression group. The MDAnderson Temador results allows me the opportunity to add a little to that past discussion. Recently I read a gigantic phase 3 study done on Surgery + Radiation + Temador w/S.O.C. dosing versus Surgery + Radiation + Temador w/dose dense therapy. (See Link Below). It was conducted by MD Anderson, and here is the critical part, while the two different dosing regimens were not statistically different in efficaciousness, MDAnderson also looked at Methylated tumors v. Unmethylated tumors, regardless of which dosing the patients received.
http://www.slaop.org/pdf/74723.SNC%20DoseDense%20Temozolomide%20for%20Newly%20Diagnosed%20Glioblastoma%20A%20Randomized%20Phase%20III%20Clinical%20Trial.pdf
Again, while the dosing did not statistically make a difference for the standard of care dosing v. dense dosing, the methylated v. unmethylated was significantly statistically different -- regardless of dosing. However, the difference in PFS was not even close to the difference most researchers previously found in much smaller trials. 8.7 months for the methylated v. 5.7 for the unmethylated.
Why is this really important for the phase 3 trial results that are 'delayed?' How does this knowledge help us as we wait?
91% of Pseudoprogressive (I am referring to "pseudo-progression" as after the real progression tumors are filtered out) tumors are methylated. Other statistics come into play here, but basically from this huge MDAnderson trial, I can fairly confidently predict that the pseudo-progression Standard of Care group will only have about 9 months PFS. This is far lower than many thought might be possible before this 833 patient study was released less than 6 months ago.
This likely means that the pseudo progression events for the control group in our phase 3 trial are (sadly for control patients) rapidly ticking off, and remember, the clinic openings skyrocketed over the past 18 months. Also recall Linda keeps stating they can power this to 4 or 5 months if it becomes necessary (remember, because of the long tail effect in the primary group, I expect far more separation for the primary endpoint in that analysis), but she does not know if they will have to increase the power. Thus the significance of the MdAnderson Temador dosing trial results from less than 6 months ago relate to our trial in that:
1. The control group in the pseudo-progression analysis of our trial is not likely to have a surprisingly high PFS median, as some critics previously projected.
2. Separation between DCVAX-L and the control group within the Pseudo-progression patients is likely to occur relatively fast, and it if it not fast enough, NWBO can power the trial to speed this group up.
Because again, while the Pseudo-progression group is not part of the Primary Endpoint analysis, it is very critical for the GBM population of patients in order to assist NWBO in convincing the FDA to use DCVAX-l for a broader application and thereby save the lives of far more people in the future.
Dok,
In addition to marking tumors for attack by the immune system, I agree that antibodies also have significant, but as we know, limited abilities to disable some tumors and/or make them more vulnerable to things like T-Cell attack. I should have included that information as well, and its significance in my discussion about your original question. Still, the thrust of my my premise remains unchanged.
I'll try to elaborate or more precisely substantiate my discussion, in additional areas that you addressed, sometime today or tomorrow.
Direct is being tested on brain cancer that metastasized to the brain. I don't know if they are injecting some of those tumors directly or hoping for a systemic response. My best guess would be that they would try to make at least one of the multiple injections directly into a brain tumor (if the size and location allow) -- as well as any breast tumors (of course) and metastasized regions additional to the brain.
I also have reason to believe that at least someone in the miscellaneous phase 1 trial may be a glioma patient.
So, your theory could be tested sooner than you think.
Wow, Sentiment Stocks. Timely find!
I was particularly impressed that the presentation was just a couple days ago.
The head of the US agency that approves medicines Friday called for more regulatory flexibility and “a new era of partnership” with the biopharmaceutical industry in bringing new treatments to patients. -- http://betaboston.com/news/2014/04/04/fda-chief-calls-for-a-new-era-of-partnership-with-biotech-firms-at-conference/
Dok, Here was your specific question.
The system I know about is local. The dendritic cells, which do travel throughout the body as well as the skin, report an antigen find by traveling to the nearest lymph node, which are mostly, but not exclusively located in the periphery. But at that point something must happen to report the antigen presence to all the other lymph nodes as quickly as possible. Some type of messenger cells. Maybe a faster form of dendritic cells or maybe some other cell. And what routes do they take?
I think it's possible….
Great Britain announces their version of the hospital exemption.
More European clinics open.
Direct trial expansion into Europe. Clinic Opens.
Clarification on the DCVAX-L trial design/delay.
Phase 1 enrollment complete for Direct.
Zero all the way up to all of these could happen next week.
(Recently, NWBO has been repeating the Direct trial will include at least 6 in each subgroup for phase 1. Take from that what you will.)
Dok, I'm still processing that question we talked about. It's been another busy weekend.
Barnstormer, As a general rule, ASCO discourages submission of abstracts that report interim data from studies that are continuing to accrue patients (examples include phase I studies where recommended phase II dose is not yet determined, or phase II studies that are not fully enrolled). Acceptance of such abstracts will be considered on a case-by-case basis.
Here is how high the hurdle was for NWBO to get their abstract accepted into ASCO, for a data presentation (not a TIP Poster). But….NWBO Did It!!!
And as stated earlier, I expect the info to be shared at ASCO very up-to-date.
The ASCO Presentation includes data through May 19, 2014.
Oral Abstract and Clinical Science Symposium Presenters: Please ensure that the discussant for your abstract has the most up-to-date data regarding your research by uploading a preliminary set of your presentation slides by Monday, May 19, 2014 or by contacting the discussant directly.