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NVS claimed to deliver 10-50 fold few CART T cells. That means they can find 2 mil. non exhausted T cells and turn them into CART T in 2 days from the patient's blood draw. DTIL may be doing the same using their optimized process with the blood from health donors.
The target YESCARTA dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 108 CAR-positive viable T cells.
Is NVS picking CD39-CD69- t cells? Which alloc CART T in clinical trial is CD39-CD69-?
Hi NY1972, ARCUS is superior in soooo many ways. Precision Biosciences is the winner in the long term.
I will never get why Wallstreet sometimes buries the best and elevates the rest. Don’t get me wrong the advanced programs of CRSP, INTL and ALLO deserve credit, but the risks are high. Higher than DTIL. That is for ding dong sure.
Ticking time bomb? monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations
https://www.nature.com/articles/s41467-021-26788-6
Too many biotechs were fat pigs destined for slaughter. DTIL is actually 2 bios. $1 for allo CART T, $1 for ARCUS.
T-charge must be a magical hotel for the wandering TILs.
Nothing I could fine. Q1 financials are on Monday.
If LD conditioning is part of the treatment, NVS should have 5-7 days to grow AUTO CART T, not 2 days.
https://ash.confex.com/ash/2021/webprogram/Paper146268.html
No, but it is used. Either fludarabine (30 mg/m2 daily for three days) plus cyclophosamide (500 mg/m2 daily for three days), or bendamustine (90 mg/m2 daily for two days).
No LD mentioned in YTB323 P1 protocol
https://clinicaltrials.gov/ct2/show/NCT03960840?term=YTB323&draw=2&rank=1
YTB323 (anti-CD19) is being tested in patients with DLBCL or CLL/SLL. For CLL/SLL in order to be potentially eligible, SD or PR after at least six months of ibrutinib, either as a second or subsequent line of therapy. As for DLBCL, relapsed or refractory after two or more lines of therapy, including auto stem cell transplant. Also, no prior CD19-directed therapy. It is given after LD chemo.
PBCAR0191 with eLD will be targeting AUTO CART relapsed pts. Stealth cells + CD3 mAb with LD will be their next gen offering for 2024.
CART T as 1st line treatment without LD?
Novartis said it used T-Charge, a new CAR-T manufacturing platform, to reduce the incubation time in vitro to 24 hours and the completion of the product to less than two days. With T-Charge, CAR-T cell expansion occurs primarily within the patient’s body (in-vivo), eliminating the need for an extended culture time outside of the body (ex-vivo)
http://www.koreabiomed.com/news/articleView.html?idxno=12767
Based on the data so far, PBCAR0191 with eLD seems to be on par with auto CAR T's. In NHL (n=17), the ORR was 71%, with a CR rate of 53%. In B-ALL (n=5), the ORR was 80%, with a CR rate of 80%. However, durability needs to improve.
Clinical data https://www.globenewswire.com/news-release/2021/12/13/2351117/0/en/Novartis-announces-T-Charge-next-generation-CAR-T-platform-with-first-in-human-data-at-ASH-2021.html
Focusing on auto doesn't make a huge amount of sense long-term.
NVS CART T needs a charge soon. Selling a salvage therapy seems to be the only viable option near term.
YTB323, an investigational, autologous CD19-directed CAR-T cell therapy developed using the T-Charge platform, showed promising results in the diffuse large B-cell lymphoma arm of a first-in-human, multicenter, Phase I dose-escalation study. Patients received a single treatment of YTB323 at two dose levels (DL). The median administered doses were 2.5×106 CAR+ cells (DL1; n=4)
If CMO can deliver 80% ORR with 50% CR in 30 CD19+ AUTO CAR relapsed pts with a flat dose and eLD, that is pivotal to me. I like the amended P1 protocol by the former Moffitt chief, it is focused.
Yes, but I think they need to be more focused as CRSP is already dosing patients in a pivotal trial, ALLO should be by mid-year, and FATE hopes to in Q4. Also, others, such as NKTX could in the next few years.
VX-880 is an allo (stem cell-derived), insulin-producing islet cell therapy. It is delivered by an infusion into the hepatic portal vein and requires chronic immunosuppressive therapy to protect the islet cells from immune rejection.
CRSP (with ViaCyte) is testing a different approach https://www.globenewswire.com/news-release/2019/09/17/1916528/0/en/CRISPR-Therapeutics-and-ViaCyte-Present-Positive-In-Vitro-Data-Towards-a-Potential-Immune-Evasive-Cell-Replacement-Therapy-for-Diabetes-at-EASD-2019.html https://www.globenewswire.com/news-release/2022/02/02/2377646/0/en/CRISPR-Therapeutics-and-ViaCyte-Inc-Announce-First-Patient-Dosed-in-Phase-1-Clinical-Trial-of-Novel-Gene-Edited-Cell-Replacement-Therapy-for-Treatment-of-Type-1-Diabetes-T1D.html
ViaCyte will also test an infusion into the hepatic portal vein. So hopefully, they and CRSP will work on immune-evasive cells for this, rather than the current approach (which requires implantable devices)
No immunosuppressive regimen needed for in vivo edit
The company also announced the VX-880 Phase 1/2 study has been placed on clinical hold in the U.S. by the Food and Drug Administration (FDA) due to a determination that there is insufficient information to support dose escalation with the product.
https://www.businesswire.com/news/home/20220502005336/en/Vertex-Provides-Updates-on-Phase-12-Clinical-Trial-of-VX-880-for-the-Treatment-of-Type-1-Diabetes
I will be interested to hear how many of the 6 AUTO CART relapsed pts are still alive. FATE 596 + CD20 not working for DLBCL pts and ALLO seems to be more concerned with safety than efficacy. DTIL is the dark horse in this race to market.
No, but I doubt the market will view it as positive.
Inserting beta-2 microglobulin gene into tumor cells with KRAS mutations using ARCUS in vivo + stealth T cells ex vivo as a combo would be game changing.
DTIL mgt. should cut burn to allow in vivo programs to catch up.
Many DNA-editing enzymes have been used to shift heteroplasmy, but they have their pitfalls in terms of potential clinical use. MitoZFN’s and mitoTALENs have a heterodimeric architecture, making packaging into viral vectors difficult, requiring that each monomer is packaged into separate viral vectors. The CRISPR-Cas9 system is not appropriate for mtDNA modification, because mitochondria do not have an RNA import mechanism33. More recently, a base editor DdCBE was shown to edit cytosines preceded by thymidines34. However, the sequence requirements limit its potential use at this time35. It has, however, recently been used to edit mtDNA in mouse embryos36. MitoARCUS overcomes disadvantages that mitoZFN and mitoTALENs present with size and viral packaging.
I guess you are expecting bad news.
Well, I won't be buying, as there is an upcoming investor event mid-year looking at data from three* (CAR-T) programs.
* PBCAR0191 with eLD chemo, PBCAR19B, and PBCAR269A plus nirogacestat (gamma secretase inhibitor).
PBCAR0191 in Patients With r/r NHL and r/r B-cell ALL trial update
Additionally, an expansion cohort is introduced into Phase 1 of the protocol to assess safety, tolerability, and clinical benefit of PBCAR0191 treatment regimens in subjects with aggressive CD19+ r/r B-cell NHLs treated with an autologous CAR T product that failed to achieve durable treatment response.
I have found some the other knockouts, which could include TET2 [1], CD95 [2], TGFBR2 [3], and regnase-1 [4]. Also, the knock-in of (incurable) IL-12 [5-7].
Refs:
1 https://www.nature.com/articles/s41586-018-0178-z
2 https://www.jci.org/articles/view/121491
3 https://insight.jci.org/articles/view/133977
4 https://www.nature.com/articles/s41586-019-1821-z
5 https://aacrjournals.org/cancerres/article/71/17/5697/568127/IL-12-Release-by-Engineered-T-Cells-Expressing
6 https://www.tandfonline.com/doi/full/10.4161/2162402X.2014.994446
7 https://www.cell.com/molecular-therapy-family/oncolytics/fulltext/S2372-7705(17)30052-9
Well, if it has been designed to overcome rejection from both T- and NK cells, as well as how it has been edited, I may make sense to add a safety (kill) 'switch.'
Given the effectiveness of a single shRNA targeting approach, the obvious next step would be to investigate targeting of multiple genes with shRNA.
CYAD previously demonstrated concurrent knockdown of up to four different genes (multiplexing) in T-cells with their first-gen shRNA scaffold. Even though this allowed the knockdown of multiple targets and was successful in terms of target knockdown, there was a reduction in transduction efficacy (with a viral vector).
This was variable between the duplex and triplex shRNA constructs, but were uniformly low when compared to the single shRNA construct. Therefore, they have been working on ways to engineer a second generation of shRNA scaffold that could enable consistent expression of duplexed and triplexed shRNAs, while improving transduction, therefore making it suitable for future clinical application.
Imitating cancer?
Gene editing is used to increase the persistence of allogeneic T cells by enabling them to evade host T cell or natural killer (NK) cell surveillance. A conventional method of preventing host T cell rejection is to knockout (KO) the ß-2 microglobulin (ß2M) to diminish the expression of MHC class I protein.
ALLO is working on a number of next-gen versions, including using CLLS's TALENs to insert the CAR into the TRAC locus. Also, signed a deal with Antion Bio for its miCAR constructs. This allows them to silence up to six genes simultaneously, and add multiple (up to four, such as a CAR) in a single step.
Moving to CRSP*, for next-gen, they have already locked in the design and edits (four or five). Now they are designing third-gen, which will have seven or eight edits. In addition, with their own facility in Framingham have automated parts of manufacturing, started to use machine learning plus translational data, and CRISPR screens https://aacrjournals.org/cancerres/article-abstract/81/13_Supplement/1537/667455/Abstract-1537-CD70-knockout-A-novel-approach-to
* Working with NKTX on three different products. One will combine CAR-NK plus CAR-T (both could target two different antigens), as well as two CAR-NK cell products, one of which will target CD70 https://www.abstractsonline.com/pp8/#!/10517/presentation/17731 https://www.abstractsonline.com/pp8/#!/10517/presentation/17730
Preclinical Gene Editing Data on its ARCUS-Based Chronic Hepatitis B Program at the HEP DART 2021 Conference
In this preclinical study, ARCUS efficiently targeted and degraded HBV cccDNA and reduced expression of HBV s-antigen (HBsAg) by 77% in HBV-infected primary human hepatocytes. To evaluate ARCUS in vivo, mouse and non-human primate models were developed that utilized an episomal adeno-associated virus (AAV) containing a portion of the HBV genome to serve as a surrogate for cccDNA. In both episomal models, a robust decrease in AAV copy number and high on-target editing in remaining AAV was observed, and a durable 96% reduction of HBsAg was further observed in mice.
See page 37 for abstract.
https://static1.squarespace.com/static/5c912d7af8135a45d18dd805/t/61aa80a73f24a36f20f71eca/1638564010806/hepdart-2021-abstract-book-final%5B26%5D.pdf
Thanks for posting, JonDoe. Although this looks like an exciting potential enhancement, it seems pretty far off at this point. My guess is that there is still animal work to be done before trying tuis in humans. Do you gave any idea of the stage in development at thus point?
It is quite exciting to see how engineering can be employed with the ability to genetically modify in or out. Add these kinds of improvements to the stealth advancements and sprinkle in multiple antigens and CAR-Ts are here to stsy. You know I love the dendritic cell vaccine technology, but the two don’t have to be mutually exclusive. Cancer treatments are about to take a giant leap into the future and CAR-Ts have only just gotten started.
Upcoming event https://www.businesswire.com/news/home/20211206005827/en/Precision-BioSciences-to-Host-Virtual-Webcast-and-Conference-Call-to-Review-Interim-Phase-12a-PBCAR0191-CAR-T-Data-and-Provide-CAR-T-Program-Updates-on-Saturday-December-11-2021
Link to webcast https://edge.media-server.com/mmc/p/ee8adj5p
New data at SITC. From the PR, ''In this preclinical study, ARCUS gene editing was used to disrupt the endogenous T cell receptor by inserting a transgene carrying a CD19-specific CAR and an RNAi sequence designed to specifically knockdown deoxycytidine kinase (dCK), a protein that converts fludarabine from its prodrug form to an active compound. This single-step approach generated allogeneic, fludarabine-resistant (FluR) CAR T cells. In these cells, the dCK RNAi sequence produced a 70% reduction in dCK mRNA abundance, and resistance to fludarabine was confirmed in vitro. Additionally, treatment of tumor-bearing mice with fludarabine and FluR CAR T cells resulted in enhanced tumor clearance and survival compared to mice receiving control CAR T cells alone or control CAR T cells and fludarabine.''
https://finance.yahoo.com/news/precision-biosciences-highlight-capabilities-arcus-131500889.html
https://jitc.bmj.com/content/9/Suppl_3/A149
ASH abstracts
Preliminary Safety and Efficacy of PBCAR0191, an Allogeneic ‘Off-the-Shelf’ CD19-Directed CAR-T for Patients with Relapsed/Refractory (R/R) CD19+ B-ALL https://ash.confex.com/ash/2021/webprogram/Paper153166.html
Allogeneic CAR-T PBCAR0191 with Intensified Lymphodepletion Is Highly Active in Patients with Relapsed/Refractory B-Cell Malignancies https://ash.confex.com/ash/2021/webprogram/Paper150609.html
Looks as though the entire gene editing market took a hit with the news of Allogene’s HOLD for their Car-T program…I am not certain this is a bad thing at all for Precision Biosciences. Time will tell but this could be a process specific issue.
PR's https://www.businesswire.com/news/home/20210909005318/en/Precision-BioSciences-Outlines-Clinical-Development-Strategy-for-In-Vivo-Gene-Editing-Pipeline
https://www.businesswire.com/news/home/20210909005309/en/Precision-BioSciences-and-iECURE-Announce-License-and-Collaboration-Agreement-to-Develop-ARCUS-Based-Gene-Editing-Therapies
Slides https://investor.precisionbiosciences.com/static-files/2f4e5170-538d-4633-acfa-aad7b65a1df3
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