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please post full times article
Jondoeuk:So the corollary is, "by what amount can DC Vax increase these low response rate?"Thanks.
to what degree can dc vax increase Obdivo's response rate?
what % of Obdivo patients respond?
Obdivo is projected by Credit Suisse to have revenues of $12 billion in 2023.That's 50% of bmy's revenues that year.If about 15-25% of all patients given Obdivo respond and that can be increased significantly by DC Vax, then what is the value of Dc Vax to BMY?
You asked for thoughts. To recap our conversation, I can think of several possible announcements that have some basis in fact. xxx has been to The Hill. What if they announce government funding for a trial with BMY/MRK checkpoint inhibitors that involves both the Direct and the Lysate procedures? xxx has said there are several possible funding sources. One might be the government. With Woodford still on board, why not announce what must be positive investigation results? He has been raising cash "to take advantage of severely depressed situations". To your point, why wouldn't he buy more stock with good trial and/or investigation news? Those who own the $3 options should also want to exercise with their $17 M if the stock rises. The EU/UK price negotiations have been going on long enough for resolution. The same goes for the P3 hold on "L" trial screening. Maybe there will finally be clarification of these items. It is overdue, because the P3 trial is officially scheduled to end in September. Maybe a combined EU/UK/FDA approval is partly cause for the delay? The company has had time to expand the Tennessee facility, but may be going slow for financial reasons, although a crowded Cognate parking lot has been reported by a Memphis resident on the Yahoo message board. xxx continues to stress that DCVax has the advantage of being a broad spectrum immune system activator. The application of this in the treatment of the many types of highly diverse solid tumors seems logical. It is becoming apparent that DCVax treatment of certain cancer subtypes will need checkpoint inhibitors to be effective, and a patent application has been made and accepted. Lately, the association of macrophages and PD-L1 has been recognized. NWBO and UCLA seem to be getting there technically, and it is time for Wall Street recognize the growing potential, especially the huge upside of the BMY/MRK partnerships. Lots of maybes here, but after all, Prins did say that the combination therapy caused the cancer to "disappear", at least in mice. Maybe the combination trial will delay commercialization of "L"? Maybe a special mesenchymal approval will be granted? Maybe we will hear something this week?
Sent from my iPhone
I believe 15% of patients responded to Obdivo in the first approved indication.By adding dc vax,as in the upcoming combo trial discussed by Prins, what do you think the 15% would increase to? Thanks.
what % of cancer patients respond to Obdivo? http://www.curetoday.com/articles/fda-expands-opdivo-approval-in-lung-cancer
http://www.businesswire.com/news/home/20160123005053/en/Bristol-Myers-Squibb%E2%80%99s-Opdivo-nivolumab-Yervoy-ipilimumab-Regimen Obdivo is projected by Credit Suisse to have revenues of $12 b in 2023, 50% of the bmy $24 b total.When Obdivo was approved first over a year ago, the response rate was 15%.According to the Prins video, the obdivo/dc vax combo trial should "start very soon.".Did Prins say by how much he expected the Obdivo response rate to improve , given the additional treatment of dc vax to the patient.
Could this BMY /ucla program pay for the dcvax obdiva combo trial?NEW YORK--(BUSINESS WIRE)-- Bristol-Myers Squibb Company (NYSE:BMY) today announced that they have entered into a collaboration agreement with UCLA as part of Bristol-Myers Squibb’s Immuno-Oncology Rare Population Malignancy (I-O RPM) research program in the U.S. The I-O RPM research program is a multi-institutional initiative with academic-based cancer centers focused on the clinical investigation of immuno-oncology therapeutics as potential treatment options for patients with high risk, poor prognostic cancers, defined as a rare population malignancy.
Bristol-Myers Squibb and the David Geffen School of Medicine at UCLA will conduct a range of early phase clinical studies as part of the I-O RPM research program, and Bristol-Myers Squibb will fund positions within UCLA’s fellowship program in the UCLA Division of Hematology/Oncology.
“The I-O RPM research program is an important complement to Bristol-Myers Squibb’s broad research and development program for immuno-oncology,” said Laura Bessen, M.D., head of U.S. Medical, Bristol-Myers Squibb. “We look forward to working with UCLA in an effort to continue advancing the science in this innovative field of research and cancer treatment.”
About I-O RPM
Immuno-oncology is an innovative approach to cancer research and treatment that is designed to harness the body’s own immune system to fight cancer. The I-O RPM research program focuses on significant areas of high unmet need marked by poor outcomes among patients with rare population malignancies. A rare population malignancy is a subpopulation within a higher incident disease population. These patients have aggressive disease with an increased potential for early metastasis to multiple sites and/or are initially refractory or subject to early recurrences with conventional cancer therapies. Existing clinical research provide a strong rationale for further research into the potential of immunotherapies for these cancers.
The I-O RPM research program is a multi-institutional initiative with Robert H. Lurie Comprehensive Cancer Center ofNorthwestern University and the Northwestern Medicine Developmental Therapeutics Institute, Moffitt Cancer Center,The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and now UCLA. I-O RPM builds on Bristol-Myers Squibb’s formation in 2012 of the International Immuno-Oncology Network (II-ON), which is a global collaboration between Bristol-Myers Squibb and academia focused on facilitating the translation of scientific research findings into clinical trials and, eventually, clinical practice.
Begin forwarded message:
https://finance.yahoo.com/news/kite-pharma-announces-review-national-181500347.html Any implications for nwbo from KITE's press release today?
Can Woodford buy more stock in nwbo before the Phase V investigation report by NWBO is released?
I've just watched the talk. Here's a running list of things that popped out to me.
1. The use of a broad immune activator is certainly beneficial when immune escape can occur after targeting a single tumor antigen.
2. If it were me, I would pay more attention to the specific tumor antigen. In particular, I'd want to ensure that the tumor preparation of freeze/thaw then feed to DCs isn't selectively eliminating a large proportion of antigens that would be immunogenic against the tumor. This is a lot of background work for the academics, similar to the mitochondria purification work I shared with you out of UPenn.
*I see that I spoke too soon. The slide at ~24 minutes highlighting the paper by Schreiber and Schumacher is incredible. I've looked through it briefly as well as the 2014 Nature paper from Schreiber on checkpoint inhibition and T cells responding to mutant proteins. This is certainly the way forward, and I'll look into it further the next moment I have the time.
3. At 7:30, he indicated that they think it is naive T cells that DC Vax will be activating. However, the best clinical responses occurred when resident T cells were present in the tumor. The ideal combination of therapies will differ if DC Vax is primarily activating naive T cells or if it is re-invigorating pre-activated T cells.
But then at 14:15 he talks about 'reactivating' the response in the mesenchymal sub-type tumor patients.
CD4 helper T cells (needed to promote the right type of response for both other types of T cells and antibody-producing B cells) and CD8 killer T cells may be responding differently. As always, if what they are doing works in the clinic, that's what really matters, but the timing and type of combination therapies could be improved if they knew what T cells were being activated.
Last thing here is T cell trafficking. The draining lymph node environment and signals acquired by the DCs from the tissue help to instruct the different chemo-attractant (chemokines) receptors that are expressed by the T cells. These help the T cells to traffic to and remain within certain tissues. By injecting in different sites and/or providing the right signals to the DCs during their maturation during manufacturing or at the time of injection could increase the proportion of T cells that get to the brain to do their job.
4. In the mouse model, he shows PD-L1 expression on innate immune cells then switches to the clinic at around 17:50 to discuss PD-1 expression on T cells. Then at 18:58 when talking about mechanism, his slide indicates that there is 'no pre-existing response'. However, as in point #3 above, he states that T cell presence in mesenchymal tumors prior to treatment is associated with improved overall survival. 13:54 - mesenchymal have a higher T cell count even before therapy starts...
He then goes on to downplay the need for pre-existing T cells when giving DC Vax + PD-1 blocking Ab. Thus, he's strongly indicating that they think the combination therapy has a good chance to increase survival of pro-neural and proliferative sub-type patients that DC Vax alone has not benefited. We'll see if he's right.
So overall, this is starting to look very promising! I do wonder if activating T cells in vitro is the long-term way forward so as to avoid the impact of radiation and proliferation inhibiting chemotherapy. Of course, these could quickly be eliminated as the standard of care, as well.
but nwbo has the combo patent application.http://www.freepatentsonline.com/20150273033.pdf
$22m on 10k at 12/31, plus $10m raised in Jan.Then burn $12m per quarter, so $22m at the end of March.Enough to get to October 1.
I believe it is against mrk and bmy policy to comment informally to random incoming phone calls / emails/texts..I believe they communicate only via public press releases/ presentations/conference calls.
at what time are bmy/ mrk mentioned
Flipper 44:how important is this patent application?
United States Patent Application 20150273033
just posted what I think Linda Liu will update this friday.
J Immunother Cancer. 2014 May 13;2:10. doi: 10.1186/2051-1426-2-10. eCollection 2014.
Cytokine responsiveness of CD8(+) T cells is a reproducible biomarker for the clinical efficacy of dendritic cell vaccination in glioblastoma patients.
Everson RG1, Jin RM1, Wang X2, Safaee M1, Scharnweber R1, Lisiero DN3, Soto H1, Liau LM4, Prins RM5.
Author information
Abstract
BACKGROUND:
Immunotherapeutic approaches, such as dendritic cell (DC) vaccination, have emerged as promising strategies in the treatment of glioblastoma. Despite their promise, however, the absence of objective biomarkers and/or immunological monitoring techniques to assess the clinical efficacy of immunotherapy still remains a primary limitation. To address this, we sought to identify a functional biomarker for anti-tumor immune responsiveness associated with extended survival in glioblastoma patients undergoing DC vaccination.
METHODS:
28 patients were enrolled and treated in two different Phase 1 DC vaccination clinical trials at UCLA. To assess the anti-tumor immune response elicited by therapy, we studied the functional responsiveness of pre- and post-vaccination peripheral blood lymphocytes (PBLs) to the immunostimulatory cytokines interferon-gamma (IFN-?) and interleukin-2 (IL-2) in 21 of these patients for whom we had adequate material. Immune responsiveness was quantified by measuring downstream phosphorylation events of the transcription factors, STAT-1 and STAT-5, via phospho-specific flow cytometry.
RESULTS:
DC vaccination induced a significant decrease in the half-maximal concentration (EC-50) of IL-2 required to upregulate pSTAT-5 specifically in CD3(+)CD8(+) T lymphocytes (p?<?0.045). Extended survival was also associated with an increased per cell phosphorylation of STAT-5 in cytotoxic T-cells following IL-2 stimulation when the median post/pre pSTAT-5 ratio was used to dichotomize the patients (p?=?0.0015, log-rank survival; hazard ratio?=?0.1834, p?=?0.018). Patients whose survival was longer than two years had a significantly greater pSTAT-5 ratio (p?=?0.015), but, contrary to our expectations, a significantly lower pSTAT-1 ratio (p?=?0.038).
CONCLUSIONS:
Our results suggest that monitoring the pSTAT signaling changes in PBL may provide a functional immune monitoring measure predictive of clinical efficacy in DC-vaccinated patients.
KEYWORDS:
Dendritic cells; Glioblastoma; Phospho-flow cytometry; T cells; Tumor immunity; pSTAT-5
PMID: 24883189 [PubMed] PMCID: PMC4039989 Free PMC Article
Share (ll will update this friday)
This is all making a lot of sense. In both the phase 2 and 3 trials, issues with the controls (dropping out or being switched to the test group, respectively) were the problems rather than vaccination effectivity.
The part in red describes what I want to highlight from my literature research - continued, iterative testing of the way that the DCs are matured, how they are fed antigen, what that antigen consists of, and where the DCs are injected is essential to getting the most out of this approach. The very good news is that there's solid results despite not yet having each of these variables optimized.
Also, the use of patient tumor as antigen is both time consuming and flexible. The costs will be tough to drive down, but you can imagine nearly any cancer being a good candidate for this approach. It doesn't matter if you don't know the cell types, precise mutation sequence data, and expression profile of the tumor. Just feed the tumor to the DCs and let them figure it out with the resident T cells. Add a boost via checkpoint inhibitors or another cancer drug, or all of the above, and there's a good chance of success.
Cheers xxxx
Sent from my iPhone
Also, here is the transcript......
Key part with exact transcript:
The issue is because we have vaccine made for everybody and we are kinda doing a somewhat invasive procedure on these patients, the FDA actually required us to have a cross over arm when the patients progress.
So uh interestingly, the whole cohort actually, um, has not yet reached, uhh you know, its, I guess, um, its pre-determined event, um, how do I say this, pre-determined number of events. Um and it seems like everyone’s living longer than we would be expecting. So in reality, I think, you know, what we’re really comparing now is actually early DC Vaccination versus later DC Vaccination (big smile). And um, and I guess it’s a good thing that the patients are living longer (laughing), but it’s not really helping our study, because if the patients didn’t get anything, hopefully, the differences would be bigger. So that’s kind of another lesson learned about these trials. We have to consider all these different moving parts.
Um, it was difficult to, it’s certainly more difficult to enroll a patient without the cross over arm because they are going through this invasive procedure, and then tell them we’re making vaccine for you but then we’re just throwing it away. You know it would be difficult.
But so anyway, we’re still in the middle of this trial, it’s still blinded, and I actually don’t have any data for you right now.
The following are some notes taken on the rest of the presentation:
Tumor comes back by 6 months to a year
cell kill
Median survival even now is probably about two years.
PI/II DC Vac… 2011
25% of patients were still alive in 2011 and are alive today in 2015
n=23
1 year - 91% alive
2 years - 55%
3 years - 47%
Stupp
1 year - 69%
2 years - 34%
3 years - 20%
Usual 5 year survival is less than 5%
Different ways of pulsing tumor cells
ATL-DC
GAA-DC
Tumor Lysates
Targeted Antigens
In the end, we’re back to using ATLs (Autologous Tumor Lysates) from patients simply because if you look at the over all survival
Could be the antigens chosen for the targeted antigen trial were not the dominate epitopes or the major drivers for these tumors
Survin
Her-2
GP100
They are present in GBM, could be they weren’t the important ones
IMUC-107 targets AIM02, MAGE-1, TRP-2, gp100, HER-2, IL-13Ra2
What we are learning now with our mutunome sequencing of our GBM tumor samples is that probably are not just a few mutations, they are hundreds if not thousands of mutations. So it could be that targeting just on or two or three or four may not be enough. So we are to this day using patient’s ATL samples.
Protocol
Surgery
8 weeks later
Leukapheresis where we culture the DCs
6 weeks of radiation with temazolamide (Temordar) chemotherapy
As they are going through that standard treatment, the DCs are being pulsed with the tumor lysates and then goes through the QA
Patients undergo 3 biweekly injections then a booster injection initially every two months and then space them out as time goes on
THis is all done by a company in Tennessee that collects the leukapacs, collects the tumors, and then ships out the actual product to the sites. Makes it quite easy for the site investigators to carry this out.
1999 FDA grants first IND - that took all the animal studies to get that IND
Went to first P1 trial
Then on to 2nd P1 trial
Then on to 1st P2 trial in 2006
Began collaborating with NWBO and they helped initiate the multi-center P2 trial in 2007
(NON BLINDED but randomized)
Leukapheresis is quite expensive - so the placebo patients were NOT getting the leukapheresis and when they knew this, they were dropping out of the trial.
Re-started back up in 2010 as a P2 and got some good initial data that went on currently to a P3 trial in 2012.
notes from Linda Liau 10/15/15 presemtation:The issue is because we have vaccine made for everybody and we are kinda doing a somewhat invasive procedure on these patients, the FDA actually required us to have a cross over arm when the patients progress.
So uh interestingly, the whole cohort actually, um, has not yet reached, uhh you know, its, I guess, um, its pre-determined event, um, how do I say this, pre-determined number of events. Um and it seems like everyone’s living longer than we would be expecting. So in reality, I think, you know, what we’re really comparing now is actually early DC Vaccination versus later DC Vaccination (big smile). And um, and I guess it’s a good thing that the patients are living longer (laughing), but it’s not really helping our study, because if the patients didn’t get anything, hopefully, the differences would be bigger. So that’s kind of another lesson learned about these trials. We have to consider all these different moving parts.
Um, it was difficult to, it’s certainly more difficult to enroll a patient without the cross over arm because they are going through this invasive procedure, and then tell them we’re making vaccine for you but then we’re just throwing it away. You know it would be difficult.
But so anyway, we’re still in the middle of this trial, it’s still blinded, and I actually don’t have any data for you right now.
The following are some notes taken on the rest of the presentation:
Tumor comes back by 6 months to a year
cell kill
Median survival even now is probably about two years.
PI/II DC Vac… 2011
25% of patients were still alive in 2011 and are alive today in 2015
n=23
1 year - 91% alive
2 years - 55%
3 years - 47%
Stupp
1 year - 69%
2 years - 34%
3 years - 20%
Usual 5 year survival is less than 5%
Different ways of pulsing tumor cells
ATL-DC
GAA-DC
Tumor Lysates
Targeted Antigens
In the end, we’re back to using ATLs (Autologous Tumor Lysates) from patients simply because if you look at the over all survival
Could be the antigens chosen for the targeted antigen trial were not the dominate epitopes or the major drivers for these tumors
Survin
Her-2
GP100
They are present in GBM, could be they weren’t the important ones
IMUC-107 targets AIM02, MAGE-1, TRP-2, gp100, HER-2, IL-13Ra2
What we are learning now with our mutunome sequencing of our GBM tumor samples is that probably are not just a few mutations, they are hundreds if not thousands of mutations. So it could be that targeting just on or two or three or four may not be enough. So we are to this day using patient’s ATL samples.
Protocol
Surgery
8 weeks later
Leukapheresis where we culture the DCs
6 weeks of radiation with temazolamide (Temordar) chemotherapy
As they are going through that standard treatment, the DCs are being pulsed with the tumor lysates and then goes through the QA
Patients undergo 3 biweekly injections then a booster injection initially every two months and then space them out as time goes on
THis is all done by a company in Tennessee that collects the leukapacs, collects the tumors, and then ships out the actual product to the sites. Makes it quite easy for the site investigators to carry this out.
1999 FDA grants first IND - that took all the animal studies to get that IND
Went to first P1 trial
Then on to 2nd P1 trial
Then on to 1st P2 trial in 2006
Began collaborating with NWBO and they helped initiate the multi-center P2 trial in 2007
(NON BLINDED but randomized)
Leukapheresis is quite expensive - so the placebo patients were NOT getting the leukapheresis and when they knew this, they were dropping out of the trial.
Re-started back up in 2010 as a P2 and got some good initial data that went on currently to a P3 trial in 2012.
please post the entire linda liau 10/15/15 presentation transcript.thanks.
thanks for the reply.do you think the entire transcript of Linda Liau's 10/15/15 presentation is posted on ihub, or anywhere on the web?I am trying to get it to my consultant, as I am a non medical.
please post the Linda Liau 10/1515 transcript. thanks.