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Latest preclinical publication points to why the DLBCL pt experienced progression-free interval of 161 days @ .05 mg/kg which is only 25% of the selected dose.
you only have to bind to a smattering of the CD47 on tumor cells to produce a response
http://www.siliconinvestor.com/readmsg.aspx?msgid=30855094
Can FV162 cross BBB?
Celgene acquired a proteasome inhibitor, marizomib (MRZ), which is in development for glioblastoma and relapsed and/or refractory multiple myeloma.
https://globenewswire.com/news-release/2016/11/18/891185/0/en/Triphase-Accelerator-Announces-Acquisition-of-its-First-Compound-Marizomib-by-Celgene-Corporation.html
aNK Cell Therapy in patients With MCC
aNK cells are derived from a human, IL-2–dependent NK cell line that was established from the peripheral blood mononuclear cells of a 50-year-old male diagnosed with non-Hodgkin lymphoma8
http://nantkwest.com/wp-content/uploads/2016/11/SITC-2016_FINAL-Nov-7.pdf
10/31/2016 317,798 Shorted
09/30/2016 19 Increased Institutional Holders
991,465 Increased Total Shares Held
Read more: http://www.nasdaq.com/symbol/tril/institutional-holdings/increased#ixzz4QE69WBNh
Recruiting- Trial of Hu5F9-G4 in Combination With Rituximab in Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma
Let see if they bought any last week? Are these guys lucky or smart or both?
TRIL 413,697 $ 6,120,000 0.06% 0.02% UP 201,905, 95%
25 cents PS for TTI621, Stanford science and CD47 research.
Thrombocytopenia SE of targeted therapies
http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia--chronic-lymphocytic-treating-targeted-therapy
Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors
http://jitc.biomedcentral.com/articles/10.1186/s40425-016-0164-7
This sounds like an oxymoron to a newbie like me. Are these mAbs designed to minimize toxicity in the expense of efficacy?
SRF231 does not enhance phagocytosis or induce hemagglutination of human or cynomolgus RBC, despite binding to these cells
No way I join twitter. Who wants to be called pumper every time SP drops.
Two novel candidates that predict the sensitivity of cancer cells to TTI-281 were identified: BCLAF1 (prediction accuracy: 83.3%) and HAPLN2 (prediction accuracy: 88.9%). Restricting the analysis to leukemia cells and including a third biomarker candidate gene (BCL2L1) improved the prediction accuracy to 100%.
https://ash.confex.com/ash/2016/webprogram/Paper94623.html
TTI-281 reduced tumor growth in a dose-dependent manner in this MM xenograft model. At 30?mg/kg/day, TTI-281 led to a statistically significant decrease in tumor growth compared with the vehicle control and carfilzomib (reduced tumor volume: 67% after TTI-281 treatment vs 33% after carfilzomib treatment, p<0.0003). Furthermore, TTI-281 treatment was well tolerated, with no effect on body weight or other obvious toxicity.
https://ash.confex.com/ash/2016/webprogram/Paper94739.html
21 patients v. 21 patients. 2 SD in Hu5F9 P1a. TTI621 ASH abstract showed 2 progression free patients given 25% and 50% dosage. Status of 16 patients to be reported in 4 weeks. Expect good news at ASH as CEO indicated abstract was submitted "8 years ago".
SRF231 = CC90002
TTI621 is a potent, high barrier for competitors.
SITC
P258 Combined blockade of CTLA-4 and CD47 with tumor irradiation
extends survival in melanoma
Overall survival in IR/CTLA-4 was ~50 %
while the combination of IR/CTLA-4/CD47 blockade was 75 % at
50 days.
P282
Inflammatory activation via PKC-Syk pathway in macrophages
lacking CD47-SIRPa restraint initiates potent phagocytosis
toward cancer
Treatment of macrophages with IL-17, LPS, IL-6, IL-1ß or TNFa,
but not IFN?, markedly initiates potent phagocytosis toward self
which leads to macrophage-mediated eradication of B16, LLC, MC38,
and EL4 cancer cells, providing an absence of the CD47-SIRPa restraint.
P308
A CD47-blocking oncolytic vaccinia virus for cancer therapy
only
SIRPa-Fc-VV was able to induce M1 and M2 macrophage killing.
Based on our encouraging in vitro experiments, we have initiated
in vivo studies to test the safety and efficacy of SIRPa-FcVV
in the MC38 C57BL/6 model.
P403
Anti-CD47 monoclonal antibody SRF231
SRF231 shows potent in vivo antitumor
efficacy in preclinical models either as monotherapy or in
combination settings. SRF231 is currently in IND-enabling studies
and is expected to enter clinical trials in 2017
P23
Chimeric antigen receptor macrophages (CARMA) for adoptive
cellular immunotherapy of solid tumors
Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam
Kim, John Scholler, Carl H June, Saar Gill
Center for Cellular Immunotherapies, University of Pennsylvania
Laden's 10K words report is no match for someone's 100 words tweet who has 50K followers. Thanks to the tweet pointing to potential safety issue, I doubled my position.
Who bought those 2.5 mil shares?? Most newbies probably sold for tax deductions. What fund managers would want to show TRIL in their portfolios?
10 mg/Kg Hu5F9 weekly not working? 47 still searching effective dose in 2 new combo trials.
Do you see that as a sign of confidence in .2 ?
Let's not forget 2/5 on .3 mg/Kg remained on study after the initial transfusion. It is going to be a balancing act between devouring tumor and sparing platelets. 47 probably wish Hu5F9 showed that activity in their P1 study. I guess .2mg/Kg is a compromise based on the following observation:
2 patients on 150% selected dose have 25% drop in platelet count after 4 weeks.
1 patient(168 days) on 25% selected dose have 25% drop in platelet count after 24 weeks.
1 patient on 25% dose have 40% drop in platelet count after 15 weeks
The key word as related to this AE is
Manageable, dose-dependent thrombocytopenia was likely due to increased phagocytic clearance of platelets. TTI-621 binds to CD47+ cells in a dose-dependent manner, potently yielding increases in cytokines associated with augmented phagocytic activity.
You answered that in prior post. Thanks anyway.
"I went back and checked and the 47 drug did not show platelet drops in their primate data which is curious. I have to think it relates to the weaker Fc of their drug, which may also translate to weaker antitumor activity based on what TRIL saw preclinically (see the same slide deck referenced above)"
Trial of Hu5F9-G4 in Combination With Rituximab in Relapsed/Refractory B-cell Non-Hodgkin's Lymphoma
https://clinicaltrials.gov/ct2/show/NCT02953509?term=Hu5F9-G4&rank=4
Trial of Hu5F9-G4 in Combination With Cetuximab in Patients With Solid Tumors and Advanced Colorectal Cancer
https://clinicaltrials.gov/ct2/show/NCT02953782?term=Hu5F9-G4&rank=2
No mention of thrombocytopenia in Hu5F9-G4 P1 study??
The study is ongoing with the current cohort at 1 mg/kg followed by 10 mg/kg weekly. Hu5F9-G4-related AEs include anemia (11 G1, 5 G2), hyperbilirubinemia (5 G1, 3 G2, 1 G3), headache (9 G1, 1 G2), H on peripheral blood smears (9 G1), nausea (3 G1), and retinal toxicity on serial retinal imaging (1 G2 cotton wool spot). Most adverse events were associated with the Priming Dose and were reversible.
http://meetinglibrary.asco.org/content/162472-176
Why no thrombocytopenia AE in Hu5F9-G4 P1 study??
The study is ongoing with the current cohort at 1 mg/kg followed by 10 mg/kg weekly. Hu5F9-G4-related AEs include anemia (11 G1, 5 G2), hyperbilirubinemia (5 G1, 3 G2, 1 G3), headache (9 G1, 1 G2), H on peripheral blood smears (9 G1), nausea (3 G1), and retinal toxicity on serial retinal imaging (1 G2 cotton wool spot). Most adverse events were associated with the Priming Dose and were reversible.
http://meetinglibrary.asco.org/content/162472-176
How easy was it to start a TRIL avalanche ?
1. Dumped 1 - 2 days volume in the first 1/2 hour, about 150K shares
2. Wrote tweets pointing to some MTD transient side effect in the P1a study
The blown up chart sucked air out of the investors. A very profitable play on fear.
Dewophile:
Quote:
The DLBCL pt who experienced progression-free interval of 161 days is getting .05 mg/kg which is only 25% of the selected dose
what's potentially interesting is that this patient is seeing a real rise in hemoglobin. If this patient had cancer induced anemia which is now improving it could be some signal of efficacy. who knows maybe we get more detail on this patient at the meeting
Citrati:
Yes, I agree there are responses. The difficulty is that the cancer will be attempting progression undetected as there is not a 100% cell kill. The rate of progession will be determined by that specific immune systems ability to handle new growth. Because detection for FL is based primarily on symptom manifestion, at this point in time, it is not usually diagnosed until stage 3 or 4. If the progression free (lack of symptoms or detection) time is increased that would be significant. It is not proven that there is no progression. All that is known is that an individual can go for long stretches before symptamology is manifest.
There are not yet specific markers identified to help in identification.
I should have more accurately stated 'currently no detectable progression is the best that can be hoped for after initial treatment'.
Thus my point that anything that can lengthen the symptom free time is significant and could lead to an intervention that lasts longer. Maybe even point to a cure. Sometimes the smallest bits of information turn into something unexpectedly important. Therefore, IMO, worth keeping documentation.
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=126309058
Laden:
2 patients with G3 thrombocytopenia after the 1st dose continued to receive weekly doses of TTI-621 without bleeding or need for platelet transfusion
https://ladenburg.bluematrix.com/sellside/EmailDocViewer?encrypt=924ec257-79d5-48ae-8dcb-1acdf29185f4&mime=pdf&co=Ladenburg&id=AllUsers4Research@ladenburg.com&source=mail
bloomburton:
We expect that final phase 1a data presented at ASH will include results for
approximately 10 new patients treated at the 0.2 mg/kg dose, and more
details for the 11 patients included in the abstract (data as of July 28, 2016)
https://www.bloomburton.com/research/TRIL20161104.pdf
If you look at the % change from baseline graphs, all 3 in .05mg/Kg group had been dosed for 77 -168 days. 1 patient in .1 mg/Kg dosed for 70 days max.
https://ash.confex.com/ash/2016/webprogram/Paper89978.html
Citrati,
Thanks for your informative comment. I remain optimistic as The DLBCL/FL pts who experienced progression-free interval of 161/70 days are getting .05 mg/kg which is only 25% of the selected dose.
Notes from abstract:
The DLBCL pt who experienced progression-free interval of 161 days is getting .05 mg/kg which is only 25% of the selected dose.
Manageable, dose-dependent thrombocytopenia was likely due to increased phagocytic clearance of platelets.
Macrophage-associated cytokines, including MIP-1a and MIP-1ß, increased during the 4 hrs after infusion
TRIL- Do you think the six pts who continued to receive weekly infusions of TTI-621 were from 0.05 mg/kg (N=3) and 0.1 mg/kg (N=3) groups? The DLBCL pt who experienced progression-free interval of 161 days is getting .05 mg/kg which is only 25% of the selected dose.
From Dewophile:
re dosing - they obviously have a dose that is active. it would be nice to know if serum concentrations are in a range where they expect tumor reductions based on preclinical but it's hard to translate from mouse anyway
the PFS in the 2 patients is nice but not POC. I suppose the long period in the DLBCL pt, which is an aggressive form of lymphoma that is normally fast growing, is something. FL is indolent so frankly totally meaningless to have no progression
I do think this is an overreaction. What would you think if forty seven inc in phase 1 didn't have anemia at all? It frankly wouldn't be a good sign bc then you question the drug's activity altogether. The fact platelets are also sensitive to Cd47 inhibition and they didn't se any makes me think TRIL's drug is more active. So if I were to bet on either of these horses it would be TRIL
http://investorshub.advfn.com/boards/read_msg.aspx?message_id=126294907
Bought 4K shares below $8 as drug activity is causing low platelet count at .3mg. .2 mg is the dose selected for 1b.
CD47/SIRPa signaling regulates normal platelet turnover and clearance of platelets
http://www.bloodjournal.org/content/105/9/3577.short?sso-checked=true
TRIL: Down 40% on dose study, none see any value in early response?
one pt with DLBCL and another with FL have experienced progression-free intervals of 161 and 70 days
Today's PR probably has more info for investors than the abstract. CEO downplayed it in Leerink. 47 will have more data next week.
I believe response was seen early in P1a and CMO/CEO have been waiting for duration data to see how much $ to put in P1b. Ansell telegraphed this in July. I would call TTI621 FIC rather than BIC as it is a fluke according to CEO.
Enough data to explain why CMO bought 9K shares in May followed by Ansell saying "very promising" in July followed by CEO saying TTI621 is 99.9% of TRIL in Sept. TAM acts like body guard for the tumor, the effect should be quick and obvious if TTI621 can reverse it's role.
Something to look for in P1 patients:
CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis
http://www.nature.com/nature/journal/v536/n7614/full/nature18935.html
If ASH poster indicates PR, that means TTI621 works without anti PD1 and is not a complement. It would be the first to convert TAM phenotype from pro to foe. SP will skyrocket regardless biotech funk as the implication is huge. Who wouldn't want a piece of the fluke?