rbruf - 'a watched pot never boils' lol , in Oncs case the burners have yet to be turned on. Hoping we see see $7 after P2b official start.
"enroll pr. - Aug. ...my 'correct calls' record on the line." - too easy.
'resilient' - good choice of words and very true. The $5.52 print on 7/14 will prove to be the summer's low ..... I'm expecting a small drop next week, annual meetings do that to most companies.
The annual summer slowdown selloff - Like lemmings , bio shares fall. Bottom 1st week of Aug... year in year out. Buy your favorites. Blrx, $1.50 ? Adxs $15+ ? Qure $25 ? Trvn $5+ ? Adxs sees $12+. (Aug)
guti - more science. .... .. and I fail to see the connection to Oncs process of EP/IL-12 .....
- "GP96 alone SIGNIFCANTLY INCREASES the expression level of IL-12, .... "
- "co-addition of these recombinant proteins with GP96 increased IL-12, . ..."
- "GP96 could enhance immunity ...of rNS3 protein via production of .. .cytokines". (IL-12)
- Entered a Sponsored Research Agreement with the University of Washington to evaluate immunologic mechanism (slide #4, 7/29/15)
mlbull34 - Thanks for the heads up. A sneak peek; Fri's annual meeting. Slide 4 missed TNBC. This trial is detailed on slide 19 - The biggie, slide 23 Interim Data: Combo study, H&N, TNBC.
guti, thnks..... I like having you and furbush on the board - all that mice data got me all riled up, lol ... .no need for guti's gullible board' -. my bad. Adaptive biologics slides were extremely positive....I hope you looked them over. GL
ps--- be kind fur lol ...... give me a source for this Mrk KgA study.thnks...
furbush.....I have to run...sorry,.. a quick post - The science is not flawed, not exactly saying that.....BUT, that cute Oncs mantra "non responders into responders" - easier said than done -- will look at the science more this week - The slides always show PD-1 works in existing high til patients --- increasing the low til count and then using PD-1 is the theory - --the unproven theory. That's where the risk is, Pierce and Punit are well aware. GL
1) "Using syngeneic mouse model ....."
2) "administration of IL-12 into tumor-bearing mice can . inhibit tumor development with significant therapeutic efficacy . ... In CLINICAL TRIALS, however, the therapeutic effect has been limited by LOW EFFICACY .. . . ...... Although the reasons for the LIMITED CLINICAL EFFICACY of IL-12 in cancer patients remain incompletely understood ... . ... .. "
The non-stop mice abstracts . Is it 95% of clinical trials fail ? In other words, 95% of mice data cannot be used to predict clinical (patients, not mice) success. I know this. Does anyone else ?
- - - - - - -- - going to call this 'guti gullible board' - - - -- -- - - -
3) "antitumor activity of IL-12 could be PROGRESSIVLY INHIBITED upon continuing administration to
patients." (not with mice, patients !)
4) "advanced tumors is likely a major factor contributing TO LIMIT THE EFFICACY of IL-12–based therapies"
I read of a hedge fund that employs 21 PhD'S , microbiologists, etc., looking for bios to invest in. With two funds invested at $5.50 a share (.27 pre split) - The science of Oncs has not won over the funds. Not yet.
Lol ! ! ,you're all right rbruf ...good way for me to end the night, smiling.- 6 months worth of posts in six hours. I'm cooked. ....the (well meaning) weasl.
brian - The webinar , Adaptive Biotech slides had me falling (sliding : ) out of my chair. I will watch again this weekend...played it last night but couldn't find a way to 'stop' and study slides or move forward to Adaptive presentation - If that was clinical data, the charts, graph's proved combo will work. That's my biased opinion. I hope you will take the time to write a review, I know it will be excellent, perhaps prophetic ? hee-hee - GL
rbruf, "it's all good" - I decided to play devil's advocate , it makes for sound investing. Guti is up to the challenge - 'iron sharpens iron' comes to mind.
Yrs ago I held Snss, drug trial: vosaroxin to treat AML, Cycc drug aldoroxsubine (sp) AML trial fails ....I looked up chemical structure of both...they were nearly identical....Told the Snss board "fail, same molecule cept 1 letter" Investors laughed "one letter can make a big difference !" ......I sold waaay before the big Fail.
Imuc, ICT-107....from the ph I abstract "no effector cells found at the tumor site" - a single site trial with phenomenal results --- a nationwide ph II Fails badly.......I sold before results.
Cldn ...I find an abstract 1) Sumo1 regulates the function of Serca2a and "sumo1 is missing in heart failure patients" - Cldn is (was) running a major phII trial for heart failure, a one time injection of serca2a . Fail. Bigtime. was $28 now $1 - sold to early, but didn't lose $
I'll continue reading abstracts, and so far I haven't found 'fail' - that's nice : )
Adxs has about 200 institutional investors, no approvals, no products. Oncs has 2.
I don't know why the 'market places no value on Oncs , but, then...Adxs was trading around $7 in feb , June hit $30 ....if combo works, we are doing the same. 500m MC.
- "Although the reasons for the limited clinical efficacy of IL-12 in cancer patients remain incompletely understood, several immunosuppressive mechanisms including a Th1 to Th2 shift due to increased IL-10 production and diminished IFN- production after repetitive treatments with IL-12 could be involved"
"Immunosuppressive mechanism, Th1 to Th2 shift due to increased IL-10 production ......"
Can the production of IL-10 be inhibited ? I'll provide the questions, I don't know the answers. . . .to be continued .....
The phase I abstract, Adil Daud- 2008 . , ,. The clinical response section has results that are exceptional. Done for today, a lot of work posting/discussing the science (that's the whine, you bring the cheese, lol) - will highlight the Daud abstract on this thread. Thnks,.
Regulation of Antitumor Response by the IL-12 Family Cytokines (abstract, 2010)
- "IL-12, which consists of p40 and p35 subunits, induces proliferation of NK and T cells and production of cytokines, especially IFN-, and also enhances the generation and activity of CTLs, through activation of STAT4."
IL-12 . . . . .induces proliferation of natural killer cells and production of IFN-y -
- "IFN-, produced by IL-12, then upregulates the expression of MHC class I and II molecules, adhesion molecules such as intracellular adhesion molecules (ICAM)-1 and transcription factors such as T-box expressed in T cells"
sounds good so far ......
- "Of note, the endogenous production of IFN- is required for the antitumor effect of IL-12 in most, if not all, cases."
Guti, would be nice if we could find a paper that shows EP/IL-12 creates the "endogenous production of IFN-y" ....if it's out there, I know you'll find it : )
- "The antitumor and antimetastatic activities of IL-12 have been extensively examined in a variety of murine tumor models including melanomas . ... .. For instance, administration of IL-12 into tumor-bearing mice can delay, reduce, and, in some cases, completely inhibit tumor development with significant therapeutic efficacy in many solid tumors . ... In clinical trials, however, the therapeutic effect has been limited by low efficacy and systemic toxicities . .. . . ...... Although the reasons for the limited clinical efficacy of IL-12 in cancer patients remain incompletely understood, several immunosuppressive mechanisms including a Th1 to Th2 shift due to increased IL-10 production and diminished IFN- production after repetitive treatments with IL-12 could be involved."
- "To improve the therapeutic efficacy with IL-12 but simultaneously minimize the toxicity, several strategies have been created including targeting of IL-12 to only tumor, and coadministration with Treg cell-depleting antibodies . ..... ."
"IL-12 is one of the most potential" EOM
guti ... .will keep the science on this thread - no need for new topic
Interleukin-12: Biological Properties and Clinical Application (abstract, 2007)
- "The reasons for the limited clinical efficacy of IL-12 as a biological response modifier in cancer patients remain incompletely understood. Early clinical studies (82) showed evidence of an “adaptive response” that down-regulated the pharmacodynamics of IL-12 following the first administration of cytokine. Subsequent studies (56, 57) confirmed that the effects of IL-12 on IFN-γ levels and the frequency of circulating tumor-specific T cells were greatly reduced after the first cytokine administration. These results suggested that the antitumor activity of IL-12 could be progressively inhibited upon continuing administration to patients. Thus, a strategy of “crescendo ma non troppo” (increasing but not too much), by increasing the dose of IL-12 to overcome the tachyphylactic response, was reasonable but never tested. In addition, the immune suppression–dominated microenvironment in advanced tumors (83) is likely a major factor contributing to limit the efficacy of IL-12–based therapies"
- "effects of IL-12 .... . were greatly reduced after the first cytokine administration." -
- "antitumor activity of IL-12 could be progressively inhibited upon continuing administration to patients."
- ". . the immune suppression–dominated microenvironment in advanced tumors (83) is likely a major factor contributing to limit the efficacy of IL-12–based therapies"
"Immune suppression-dominated ..... tumors." The #1 reason for high fail rate, oncology trials. Patients are almost always stage III or IV. Locally advanced or metastatic : (
Inclusion criteria (combo trial)
1) Patients must have histological or cytological diagnosis of melanoma with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent.
guti -- I've read the above several times. Furbush and I are adversarial pumpers. You and I will be, well, just plain ol' adversaries : )
- "As a single agent, . . . . injection of recombinant IL12 exhibited MODEST clinical efficacy"
- Macrophages can SUPPRESS dendritic cell production of IL12 through the production of IL10
- We hypothesized that malignant cells alter the selective fitness landscape by locally inhibiting the biological response to IL12 = "malignant cells ....'inhibit' the biological response to IL-12"
- "Specifically, the 2D6 cell secretes both IFNγ and IL10 in response to IL12 stimulation" . As stated previously, IL-10 suppresses the production of IL-12. Could this be the reason for the increased frequency of IL-12 administration ?? The extension trial ?
- "In short, the 2D6 cell model provides a stable platform to identify factors that suppress .. .. IL12 within a variety of .... tumor cell models" . Fine, we can identify factors that suppress the bioactivity of IL-12 ....BUT, can that be done ? Overcome 'the factors that suppress'. As far as I know, no.
The last sentence . . .. . . ..shall I call it 'the final nail' ?
-" If the role of IL12 in regulating host immunity is similar in different anatomical tissues and that suppressing the activity of this network node is essential for oncogenic transformation ......"
Suppressing the activity of IL-12 (network node) ....essential for tumor cell (oncogenic) growth.
- "malignant cells that arise in these tissues will harbor RESIDUAL mechanisms to suppress the bioactivity of this cytokine." This cytokine being IL-12.
This post has helped me to understand why EP/IL-12 is not enough as a stand alone. Combo IO therapy is now the consensus of the scientist/medical community. If Oncs can prove their theory (combo trial) increased IFN-y, increased TIL production + PD-1 = clinical response, this could be a good investment.