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Link to R&D Day webcast https://event.on24.com/wcc/r/3376500/7AB08E138025EF6B119E3D8FDB9AD2BC
It will be given IV (as part of lymphodepletion) to transiently deplete activated effector T-cells, and likely with a non-stealth CAR-T cell product (they have the most clinical data on PBCAR0191). As for dose, I would imagine they will test a few different levels with sLD.
Oral administration of anti-CD3 monoclonal antibody as a potent immunomodulatory agent: preclinical and clinical studies
Whereas intravenous administration of anti-CD3 acts via transient depletion of the activated effector T cells, oral anti-CD3 mAbs act by the induction of Tregs, thus causing the immunomodulation of the CD3/TCR complex and decreasing common unwanted adverse effects associated with parenteral administration, such as CRS 61. Oral anti-CD3 mAb, unlike its intravenous counterparts, affects the gut immune system and mesenteric lymph nodes (MLNs), thus promoting Treg activity without inducing generalized immunosuppression 62. This mode of therapy uses the gut immune system and underlying lamina propria for the generation of immune signals, thereby inducing a favourable systemic immune response 23, 24.
The induction of regulatory cells has been described following oral administration of anti-CD3 mAb in mice and in humanized mice, following migration of the antibodies to the gut wall 63. The oral administration of anti-CD3 mAb in experimental autoimmune encephalitis, a model of multiple sclerosis, induces CD4+CD25– latency-associated peptide (LAP)+ T cells that exhibit regulatory properties 64, 65. Similarly, oral anti-CD3 mAb suppresses low-dose streptozotocin-induced and non-obese diabetic (NOD) diabetes models of T1D through the induction of IL-10-secreting CD4+CD25–LAP+ regulatory cells, thus decreasing T cell proliferation and IFN-? and IL-17 production and increasing TGF-ß production 66-68. Oral anti-CD3 is beneficial in animal models of colitis 69 and atherosclerosis 70.
Orally and intranasally administered anti-CD3 have been found to suppress autoantibody production in a mouse lupus model 71, 72. An increased release of IL-10 in the serum has been demonstrated and suggested to account for the protective effects of systemically administered anti-CD3 mAbs 59, 73.
https://onlinelibrary.wiley.com/doi/10.1111/cei.13159
Still need to dig in on this molecule…
Clinical trials with intravenous anti-CD3 mAb
Two Phase I safety trials in renal allograft recipients with acute rejection episodes demonstrated that otelixizumab [93] and teplizumab [94] do not elicit major side-effects. In the year 2000 the first clinical trials with humanized anti-CD3 mAb were launched to test the tolerogenic activity of anti-CD3 mAb in T1D. In an American Phase I/II trial, teplizumab treatment of patients with recent onset T1D improved insulin production and metabolic control [95,96]. Similarly, a European Phase II/III study giving up to a total of 64 mg of the anti-CD3 mAb otelixizumab over 6 consecutive days reported a long-lasting therapeutic effect in terms of ß-cell preservation, as measured by C-peptide levels [97,98]. The effect was most significant in patients that had good C-peptide levels at the beginning of the treatment [97,98]. Follow-up studies were designed to test whether a lower dose of teplizumab (two courses of 14 days treatments, each cumulating 5, 6 or 17 mg) [9] or otelixizumab (3.1 mg cumulated during 8 days) could preserve C-peptide secretion in new-onset T1D patients while decreasing the side effects that were observed in the previous studies. However, the low dose of otelixizumab was nonefficacious [99–101] and the choice of endpoints of the Protégé study testing teplizumab was highly controversial [9]. A post hoc analysis using conventional endpoints found a treatment benefit in patients with higher baseline levels of C-peptide [102]. Also the AbATE study reported that patients with new onset diabetes benefit from treatment with teplizumab for at least 2 years and identified immunologic features at baseline that were significantly different between responders and nonresponders [103]. Teplizumab is currently being tested in preventing onset of T1D in a population ‘at-risk’ (ClinicalTrials.gov; NCT01030861). A new study on otelixizumab is recruiting T1D patients to identify the concentration with maximal therapeutic effect and minimal side effects (NCT02000817, clinicaltrials.gov). While otelixizumab and teplizumab were foremost tested in patients with T1D, visilizumab and foralumab were mostly studied in IBD [92]. A first Phase I trial, assessing safety and efficacy of visilizumab in patients with severe corticosteroid-refractory ulcerative colitis gave promising results [104]. After reducing the original dose of 15 µg/kg/day for 2 days due to occurring side effects (prolonged lymphopenia) to 10 µg/kg/day the safety profile was considered acceptable. 84% of patients showed a clinical response, with 41% entering clinical remission and 44% endoscopic remission [104]. A follow-up randomized, double-blind, placebo-controlled trial that was intended to confirm the efficacy of visilizumab for the treatment of IBD (but used only half of the original dose, i.e., 5 µg/kg) was terminated prematurely because of safety and efficacy concerns [105]. Treatment with a cumulated dose of only 0.7 mg (for a patient weighing 70 kg), was not only associated with a cytokine release syndrome but also with an increased rate of infection as well as vascular and cardiac symptoms. This was surprising as administration of 48 mg otelixizumab to patients with T1D provoked less side-effects [97]. It was hypothesized that visilizumab's low tolerability as compared with other Fc modified anti-CD3 mAb might be due to a stronger activation of CD3/TCR signaling [92]. As a consequence the clinical development of visilizumab was halted. Foralumab, the only completely human anti-CD3 mAb, was assessed in a Phase I/II clinical trial in patients with moderate to severe active Crohn's Disease [106]. Intravenous administration of up to 1 mg for 5 days was considered safe with manageable side effects. Even though the power of this study was too limited to assess clinical efficacy, the dose of 1 mg seemed to ameliorate the endoscopic index score while no significant improvement of clinical symptoms as assessed by the Crohn's disease activity index was reported [106].
Clinical trials with oral anti-CD3 mAb
A Phase I study with healthy subjects showed that repeated oral administration of the anti-CD3 mAb OKT3 was safe and induced immunological effects [107]. When given orally, this FcR binding antibody did not trigger systemic proinflammatory cytokines, immunogenicity, depletion of T cells or modulation of the CD3/TCR complex. Oral OKT3 enhanced T-cell proliferation, suppressed Th1 and Th17 responses and led to increased TGF-ß/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells [107]. A treatment regime of five-times 1 mg was considered superior to 0.2 or 5 mg [107]. Two single blind randomized placebo controlled Phase IIa studies in patients with treatment resistant chronic hepatitis C infection (HCV) [108] or nonalcoholic steatohepatitis (NASH) and altered glucose metabolism that included subjects with Type 2 diabetes [109], demonstrated that oral CD3 was safe and well tolerated, as measured by blood hematology, chemistry, immunological safety markers and physical signs [108,109]. Both studies reported positive effects on disease and immunological markers including an increase of Tregs [108,109].
Thus, mucosal anti-CD3 mAb therapy is an attractive approach for the treatment of inflammatory and autoimmune diseases. Further studies are now required to investigate the therapeutic effect of oral anti-CD3 mAb and to test nasal administration.
https://www.futuremedicine.com/doi/full/10.2217/imt-2016-0049?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
This is quite the interesting opportunity…
Tiziana’s Foralumab is the world’s first and only, fully human anti-CD3 antibody and can be delivered orally, making it a potential game changer in the treatment of Crohn’s Disease and other autoimmune diseases through higher efficacy and reduced toxicity. The United States Patent and Trademark Office has granted a patent covering its proprietary formulation for oral administration. Additionally, Tiziana is employing another revolutionary approach to treat patients with neurodegenerative diseases such as progressive MS (pro-MS) by delivering Foralumab via nasal administration. Foralumab modulates the immune response, reducing inflammation locally and systemically, through interaction with the gastrointestinal and nasal mucosal immune system. Tiziana anticipates the initiation of a Phase 2 trial with nasally administered Foralumab in progressive multiple sclerosis (pro-MS) in Q2 2021. Phase 2 trial with orally administered Foralumab for Crohn’s indication is anticipated to be initiated soon
http://www.tizianalifesciences.com/drug-pipeline/foralumab/
I hear ya…. I only buy options when there’s an immediate catalyst. My HOPE is that the stock starts to move before Sept 9th and I can sell my options before that date (I alway worry about “sell the news”)
And I’m a gambler…
Unfortunately, I am fully invested and can’t free up much cash before September 9th. I have a sizable block of stock, but nowhere near where I want to be. I was hoping for some other things to pop first. I may really regret not selling all my modest biotech to buy this rocket. Diversification can be your enemy in biotech investing and I already see that I will likely regret it soon.
I don’t do options. I don’t like the time bound risk in early biotech companies. It adds an element of risk that to me is unnecessary when you are already in speculative ventures.
I concur with everything you said.
I bought a few options and own some shares.
Good luck!
Hi Patrick,, welcome aboard! Jondoeuk has provided some good intelligence and I have been trying to keep this site current. It had been a few months since Precision has had any real news. I forgot to post the latest gene news that was provided and will do so soon.
I am getting crazy excited for this stock. Their CAR-T program has unappreciated value and will be one of the players in the first and second generation allogenic products. It remains to be seen what the marketplace will shake out to look like but based on BP interest and investment in the autologous market right now, I think there is clear value here for those platforms.
To me the real juice to squeeze here is gene editing. They have clearcut advantages over CRIPR based programs. The race to deliver gene editing technology depends on how you define the game, but as far as I see it, the first in opportunities are plentiful and the companies seem to be giving each other some space right now. A better technology can be second or third to market however and still win the game. I really like where Precision is positioned.
$650M market cap? Are you kidding me? It doesn’t take too much research to see the other players are either dramatically overvalued or DTIL is significantly undervalued right now. I am pretty certain that the announcement of first human dosed with ARCUS editing will cause a spike. DMD could be very lucrative and all theirs.
Seems like no one else here is…
I own some. May buy more for 9/9
Very excited for September 9th…Gene therspy research day is just 4 weeks away,
New 8k regarding ongoing consulting relationship with former COO
https://investor.precisionbiosciences.com/node/8756/html
Good coverage of the current state of affairs as far as stock price goes for Intellia. I the Motley Fool gives a balanced viewpoint with their bias included. We should be close behind them in ATTR. The status od DMD and other genes still seams to be a footrace. Mitochondrial disease are Precision’s
https://www.fool.com/investing/2021/07/04/2-reasons-to-buy-intellia-and-1-big-reason-why-i-w/?source=eptyholnk0000202&utm_source=yahoo-host&utm_medium=feed&utm_campaign=article
ALLO is also testing nirogacestat https://www.globenewswire.com/en/news-release/2021/04/12/2208248/0/en/Allogene-Therapeutics-and-SpringWorks-Therapeutics-Announce-Dosing-of-First-Patient-in-Phase-1-Study-Evaluating-ALLO-715-in-Combination-with-Nirogacestat-in-Patients-with-Relapsed-.html
Some clinical data from 715 https://www.allogene.com/resources/download/Anti_BCMA_ALLO_715_And_Anti_CD52_Mab_ALLO_647.pdf
Also, the first TurboCAR is in the clinic (again, targeting BCMA) https://www.allogene.com/resources/download/Preclinical_Evaluation_of_ALLO_605.pdf
Others, such as ALLO are also working on so-called stealth cells. They plan to lower the levels of both MHC Class I and II. If NK cells reject the (CAR-T) cells, they can add an HLA-E transgene or scFv, which should stop it.
Also, this was in-licensed. The ADR recognises 4-1BB on the patient's activated T and NK cells, and mediates their elimination, effectively protecting the CAR-T cells from rejection https://www.nature.com/articles/s41587-020-0601-5
Clinical data testing an auto anti-BCMA CAR-T with another GSI was encouraging. The bORR was 100% (five VGPR and one PR), five were MRD negative, and at the data cutoff, no patient has relapsed, with a median follow-up of five months (range 1-11).
So this combo should improve the depth and duration of response.
CRISPR/Cas9 company Intellia and Regeneron report first in-human gene editing results in 6 ATTR patients showing positive safety and efficacy data. I had no idea that they were this far along. Pretty impressive.
https://ir.intelliatx.com/news-releases/news-release-details/intellia-and-regeneron-announce-landmark-clinical-data-showing
Precision BioSciences and SpringWorks Therapeutics Dose First Patient in Expanded Phase 1/2a Clinical Trial Evaluating PBCAR269A with Nirogacestat in Patients with Relapsed/Refractory Multiple Myeloma
Mentioned: DTIL SWTX
Precision BioSciences, Inc. (NASDAQ:DTIL), a clinical stage biotechnology company developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS® genome editing platform, and SpringWorks Therapeutics, Inc. (NASDAQ:SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, today announced that the first patient has been dosed in the combination arm of Precision's Phase 1/2a trial evaluating PBCAR269A. In the study, Precision's investigational allogeneic BCMA-targeted CAR T cell therapy will be combined with nirogacestat, SpringWorks' investigational gamma secretase inhibitor (GSI), in patients with relapsed/refractory (R/R) multiple myeloma.
"We are pleased to begin dosing patients in the combination arm of our ongoing Phase 1/2a study evaluating PBCAR269A, our first-generation allogeneic CAR T candidate targeting BCMA in patients with R/R multiple myeloma. BCMA is a well-established therapeutic target for multiple myeloma and this arm of the study pairs PBCAR269A with SpringWorks' nirogacestat, a gamma secretase inhibitor, a combination intended to offer strong mechanistic rationale for clinical benefit," said Alan List, M.D., Chief Medical Officer at Precision BioSciences. "As we look forward to sharing interim monotherapy data for PBCAR269A later this year, we are also conducting IND enabling studies to advance PBCAR269B, an immune-evading, stealth cell formulation into the clinic in 2022. We have high conviction in both our technology and BCMA as a target and we are pursuing a broad, data-driven strategy to inform our future development plans for this indication."
"We are pleased to advance this combination into the clinic so we can evaluate if nirogacestat paired with PBCAR269A offers a safe and efficacious treatment option for patients with multiple myeloma," said Saqib Islam, Chief Executive Officer of SpringWorks Therapeutics. "We have made significant progress in developing nirogacestat as a cornerstone of BCMA combination therapy across modalities and look forward to generating clinical data with all of our partners."
In September 2020, Precision and SpringWorks entered into a clinical collaboration in which Precision is sponsoring the expanded Phase 1/2a study of PBCAR269A to include nirogacestat and evaluate the safety and preliminary clinical activity of the combination therapy. Simultaneously, Precision continues to enroll patients in the highest dose cohort (Dose Level 3 at 6.0 Ã? 106 cells/kg) in its monotherapy study with PBCAR269A.
Just taking a quick look at where things were.
Avexis was a vector gene therapy company using AAV9 with 15 successfully treated human SMA babies, a few very early other MD vectors, and some preliminary CAR-T work. An inferior technology IMO with some questions of durability and long term safety. Novartis snatched them up for $8.7B.
https://www.fiercebiotech.com/biotech/novartis-inks-8-7b-avexis-buyout-to-build-gene-therapy-unit
Spark was a gene therapy company with a host of genetic eye disease vector gene therapies on market and in development with very limited revenuee from these conditions. Roche bought them for $4.3B.
https://www.fiercepharma.com/pharma/roche-to-wrap-up-4-3b-spark-deal-after-antitrust-ordeal-ends-ftc-thumbs-up
Astellas with early vector company Audentes $3B. https://www.fiercebiotech.com/biotech/astellas-inks-3b-audentes-buyout-to-expand-gene-therapy
All inferior technology for many reasons…Eli Lilly already thinks our first six genes are worth $2.6B plus royalties on sales. What is the whole platform and CAR-T program worth?
haTTR is a rare disease with currently two antisense treatment options from Alnylam (leader) and Ionis (alternative). These launched recently and adoption os as expected for a solid rare disease launch.
They come with their benefits and drawbacks which are now generating about $500M annual revenue with a 12% growth clip as these get adopted worldwide. There remains unmet medical need in this disease and there are advantages to a one and done approach. Solving how to price and recover gene editing value is another question.
https://investors.alnylam.com/press-release?id=25686
https://investor.precisionbiosciences.com/news-releases/news-release-details/new-preclinical-data-presented-2021-american-society-genetic
These Cure muscular dystrophy advocacy organizations are quite shrewd in investing research support with the dollars they raise through charitable giving. They will endorse technology in research support and clinical acceptance post safety and efficacy trials.
I love this podcast! Precisely the kind of affirmation I needed to start the day. Bioscientificaly unique advantages to ARCUS will likely have meaningfully differentiated outcomes in human practice. Precision Biosciences.
A very good podcast on gene editing for DMD and other diseases. Good to hear Precision and Lilly on the same stage. This is going to be a very lucrative relationship. If you want to learn about DMD start from the beginning, or fast forward to 17 min for the companies.
https://soundcloud.com/user-457375319-637033873/s3-ep3-gene-editing-fighting-dmd-from-every-angle
I appreciate the detailed summary of the allogenic CAR-T landscape. I was not aware that Allogene was so far along. I will have to look more closely at them. It seems to me that CRSP and NKTX are at similar stages as DTIL with the first gene tech and I think the stealth cell technology for Prcision has promise that may leap frog the first generation allogenic therapies. I like DTIL relative to them both regarding the CAR-T platform, but you are more knowledgeable here and I would appreciate your opinion.
Although, my primary interest in DTIL is their gene editing platform which I believe is superior to CRSPR technology. I need to read more thoroughly the literature on NHP use of CRSPR, but my first pass leads me to believe that off target affects will always be a hurdle with the use of CRSPR to edit genes in vivo for large animals , and especially humans. It is one thing to create animal models of disease and quite another to treat disease without serious safety risk suitable for humans. I don’t consider their hemoglobinopathy programs to be in vivo editing as they are editing stem cells ex vivo and reintroducing them to the patient. This isn’t too dissimilar to the CAR-T approach. I do think DTIL should challenge them in that space, but they would be playing catch up and would need to differentiate in some way to capture significant market share, not being first to market. These diseases likely will not command the market size that the other programs will IMO. We shall see how the current treatments being launched and late stage development programs do commercially. Perhaps, I am wrong and biased but I think these diseases will not produce blockbuster or near blockbuster revenue. The payer mix here is mostly government.
Muscular Dystrophies are a different story., as are mitochondrial diseases. There are high cost treatments in some MDs and SMA has been quite lucrative. DMD has been handicapped by therapies without demonstrated efficacy that charge very, very high prices and target small subsets of the disease. The high prices, however, are a good thing when looking to price a one and done technology. Beyond these diseases you start to look at things that are not rare or ultra-rare. That could capture crazy big revenue for multiple diseases. This is why I believe DTIL is significantly undervalued. Eli Lilly’s move to me validates my thinking. The future royalties for the six diseases is on top of sales, not profits which to me could mean significant revenue. There are many more targets available beyond these six. That gets me excited about the potential here. The other CAR-T companies don’t have this.
To me CAR-T is the fuel, but gene editing is the rocket. Appreciate your feedback. Thanks,
Dendream
Good coverage of the Lilly deal here. Lilly seems pretty excited...
I know the numbers are small, but the ORR for heavily pretreated r/rNHL that had previously received CAR-T (75%) and Stem Cell Transplantation (66%) is pretty impressive. They are focusing on eLD to delay immune response to CAR-T administration, but I think they are still looking at retreatment. Combining the two approaches could produce some strong long term results in these difficult to save patients.
Precision is leading the race to allogenic off-the-shelf CAR-T with solid phase I results. How CRSP is worth $6B and this company is only priced out at $650M is beyond me to understand. DTIL is looking at potentially $2.5B in milestone payments on the gene editing program, has $200M cash on hand and has one heck of an exciting pipeline and platforms.
Jondo, Did you see the last 5 minutes of Wednesday’s presentation? I try to watch and it freezes on me at 18:37 every time. If so, what does he say?
I love the CAR-T program and progress being made, but gene is where this game is played. The primates are adding up in numbers and years. That is very promising in my eyes. Milestones and CAR-T will not only carry this through but will likely be quite profitable. They only licensed 6 genes, only six. It doesn’t sound like T1DM is one of them???
DMD will be a very nice win, they haven’t said they have a gene yet but SMA has proof of concept and can now be ‘cured’ in babies. Type 1 Babies would show efficacy in weeks. Time is muscle in SMA and every day a Type 1 SMA baby goes without SMN, they lose muscle. Many never raise their heads, cry a cry or lift their arms without the new therapies. Spinraza and Vector gene are available but have drawbacks including IT administration or uncertainty about long term overproduction as their is an adult MD that is caused by over instead of under production. Vector could accumulate risk but natural production should be controlled. Arcus could be tried in utero even some day and they never would have to breath one diminished breath. Imagine how those 1000 parents would feel about never having to worry a single day each year. DMD is bigger. Not as bad, but not good at all. It is tough to watch your child slowly waste away.
aTTR is becoming an established market too. There is big money in curing MD of any kind but those three have cost determination for lesser technology. In the case of DMD, literally no proof of efficacy. The medical costs offset, the cost of current therapy, and the life years of income gained make quite a contribution to society. SMA kids have superior intellect. It is a unique correlation. One of them may just invent the hyperdrive or cold fusion.
The PR https://www.businesswire.com/news/home/20210604005124/en/Precision-BioSciences-Reports-Progress-on-Two-Strategies-Designed-to-Optimize-Durability-of-Allogeneic-CAR-T-Therapy-in-RR-Non-Hodgkin-Lymphoma
Slides https://investor.precisionbiosciences.com/static-files/24fbfeff-5c95-42a7-abde-9ca32b97a979
New presentation available, showcasing 12 r/r NHL patients with eLD, as well as stealth technology findings.
https://investor.precisionbiosciences.com/static-files/d09d5708-74f5-438e-8f7b-3f26e4781a87
No, but at the upcoming R&D Day they could disclose the two other targets.
PBCAR0191 CD19 Virtual Update https://edge.media-server.com/mmc/p/mscss65z
These are probably not part of the Eli Lilly deal.
https://www.nature.com/articles/s41467-021-23561-7
Currently, most mitochondrial disorders have no treatment and care is only palliative. The ability to shift mtDNA heteroplasmy is a promising treatment approach for severe heteroplasmic mitochondrial disorders. This can be done by decreasing levels of mutant mtDNA to below disease threshold levels, to ameliorate phenotypes.
In conclusion, mitoARCUS is a promising tool for eliminating mutant mtDNA. Its compact size, monomeric structure, ability to recognize new target sequences, and ability to produce large shifts with minimal negative effects suggest that it could be further developed for in vivo applications.
There will be some great clinical data this year with their CAR-T program, but this gene editing platform is really something to explore. The lipid study in primates is really fascinating. There is good durability with no evidense of off target editing that is seen with other technologies, and on lipids. They have some solid targets tested in animals, like aTTR. There are some low lying fruit in Neuromuscular disease with acceptable risk tolerance.
https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-announces-poster-presentation-upcoming
Eli Lilly may have gotten a bargain when they picked up those six conditions for $600M in milestones and single to low double digit royalties. Bargain. Especially when considering those two undisclosed conditions.
Precision is leading the way to editing genes in non-human primates (macaque monkeys). Long term safety and implantation have been confirmed over 3 years with demonstrated benefit on seromarkers of efficacy.
https://www.genengnews.com/news/preclinical-study-shows-safety-efficacy-and-durability-of-lowering-ldl-cholesterol-levels-long-term-in-non-human-primates/
I-Cre-I includes a built-in safety switch that shuts it off after a single, specific DNA edit reducing the risk of off-target edits.
The research team monitored NHPs for more than three years and have continued to show a sustained reduction in LDL-c levels and stable gene editing without any obvious adverse effects. After the single treatment, NHPs continue to show reductions of up to 85% in PCSK9 protein levels and a 56% in LDL-c levels.
“To our knowledge, this is the longest duration gene editing data in a large animal model. The data demonstrates that a single administration of an ARCUS nuclease could represent a potential one-time, permanent treatment for familial hypercholesteremia,” said Derek Jantz, PhD, co-author on the paper and chief scientific officer at Precision BioSciences.
“ARCUS has attributes that we believe significantly differentiate it from RNAi or conventional AAV gene therapy approaches, as well as CRISPR gene editing approaches. At more than three years out, we are seeing a stable gene edit that is being inherited by subsequent generations of hepatocytes, and evidence thus far supports that this is a permanent change. We look forward to continued monitoring of these animals and applying these learnings to our other in vivo gene editing programs,” says Jantz.
Jondo, I guess that I remain confused and would guess that you are not. Does the population in the ASCO abstract include those on slide 13 here or is it a different group? Are the populations on slide 36 mutually exclusive as well and if not how much overlap between the categories? If these are too explicit, I understand.
https://investor.precisionbiosciences.com/static-files/a80efc56-d16b-4892-bf83-b017b13042d2
Thanks for posting jondo, do you know if that is a new population or an update on the first set in the below?
I find the abstract results rather impressive. Am I missing something?
Thanks for posting jondo, do you know if that is a new population or an update on the first set in the below?
https://investor.precisionbiosciences.com/static-files/a80efc56-d16b-4892-bf83-b017b13042d2
I find the abstract results rather impressive. Am I missing something?
I hope they continue to build and start to screen leukopaks for genomic and cellular characteristics that correlate with favourable clinical outcomes*. Also, removes exhausted and senescent cells (both before and after production), use translational data to identify other characteristics that contribute to (durable) response, improve the ex vivo expansion, and more.
* https://cancerdiscovery.aacrjournals.org/content/early/2021/04/05/2159-8290.CD-20-1677 https://www.nature.com/articles/s41591-020-1061-7 https://www.nature.com/articles/s41591-018-0010-1
I await the data at ASCO, but they are in the lead when it comes to preventing rejection, and the first patient should be dosed in the PBCAR19B soon.
ASCO abstract https://meetinglibrary.asco.org/record/197143/abstract
Very exciting ARCUS gene editing platform recently validated by Eli Lilly has reached first in non-human primates milestone and looks to be ready to take on muscular dystrophy.
Advance ARCUS-based in vivo gene correction programs into human clinical trials. In our preclinical studies, we observed the high-efficiency and tolerability of in vivo genome editing using ARCUS in a non-human primate model, as published in Nature Biotechnology in July 2018 and Molecular Therapy in February 2021. To our knowledge, we are the first company to complete this milestone, which we believe to be critical to successful in vivo genome editing therapeutic development. We have built on this early success by diligently advancing a diverse portfolio of preclinical in vivo gene correction programs through additional large animal studies, focusing initially on gene targets occurring in the liver and eye. As discussed above, in November 2020, we also announced a research collaboration and exclusive license agreement with Lilly to utilize ARCUS for the research and development of potential in vivo therapies for genetic disorders, with an initial focus on DMD and two other undisclosed gene targets.
Whatever you may think about CAR-Ts there is a market, it is quite large, and we know there could be a lot more potential if someone can figure out how to harness them better. I have some ideas and if you know me from the other board, I bet you can think of new ways too. Again, I haven’t done much homework, but I think these guys may have a slightly better mouse trap, and again my guess is other people do too.
I have taken a long position. I am not an investment advisor. I am not an advisor of any kind. I am not offering you any investment advice. You must make investment decisions on your own. Invest at your own peril.
Details for the presentation (tomorrow) are below:
Guggenheim Healthcare Talks | 2021 Genomic Medicines & Rare Disease Day
Panel: On the Cusp of Genomic Medicine and Cell Therapy for Dyslipidemia and T1DM
Presenter: Derek Jantz, Ph.D., Chief Scientific Officer
Date: Thursday, April 1, 2021
Time: 8:00-8:50 AM ET
A live webcast of the presentation will be accessible on the Company's website, www.precisionbiosciences.com, in the Investors & Media section under Events and Presentations. An archived replay of the webcasts will be available for approximately 30 days following the presentation.
The Prognosis For Precision BioSciences
https://seekingalpha.com/article/4416084-prognosis-for-precision-biosciences
A new preclinical paper, which supports the use of DTIL's RNAi cassettes.
From the abstract: ''CD19-targeting chimeric antigen receptor (CAR) T cells have become an important therapeutic option for patients with relapsed and refractory B cell malignancies. However, recent clinical data indicate that a significant portion of patients still do not benefit from the therapy owing to various resistance mechanisms, including high expression of multiple inhibitory immune checkpoint receptors on activated CAR T cells. Here, we report a lentiviral two-in-one CAR T approach in which two checkpoint receptors are downregulated simultaneously by a dual short-hairpin RNA (shRNA) cassette integrated into a CAR vector. Using this system, we evaluated CD19-targeting CAR T cells in the context of four different checkpoint combinations—PD-1/TIM-3, PD-1/LAG-3, PD-1/CTLA-4 and PD-1/TIGIT—and found that CAR T cells with PD-1/TIGIT downregulation uniquely exerted synergistic antitumor effects in mouse xenograft models compared with PD-1 single downregulation, and maintained cytolytic and proliferative capacity upon repeated antigen exposure.
Importantly, functional and phenotypic analyses of CAR T cells as well as analyses of transcriptomic profiles suggested that downregulation of PD-1 enhances short-term effector function, whereas downregulation of TIGIT is primarily responsible for maintaining a less-differentiated/exhausted state, providing a potential mechanism for the observed synergy. The PD-1/TIGIT–downregulated CAR T cells generated from diffuse large B-cell lymphoma patient-derived T cells using a clinically applicable manufacturing process also showed robust antitumor activity and significantly improved persistence in vivo compared with conventional CD19-targeting CAR T cells. Overall, our results demonstrate that the cell-intrinsic PD-1/TIGIT dual downregulation strategy may prove effective in overcoming immune checkpoint-mediated resistance in CAR T therapy.''
http://www.biorxiv.org/content/10.1101/2020.11.07.372334v1.full
I would like to see the company testing different small molecules during ex vivo expansion of their CAR-T cell products, which could improve their antitumour activity https://jitc.bmj.com/content/5/1/26.long https://www.sciencedirect.com/science/article/abs/pii/S1535610820302543 https://www.nature.com/articles/s41467-020-20696-x
Interim data results for PBCAR0191 https://edge.media-server.com/mmc/p/m7mxxoub
Slides https://investor.precisionbiosciences.com/static-files/a80efc56-d16b-4892-bf83-b017b13042d2
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