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No mention of the primary tumor or antigen spreading which is a must for solid cancers.
How about inserting MMR gene into MSI cancers and knock out gene expressing IL-1R1?
Hutch researchers scanned specimens representing 21 different cancer types. Looking only for the gene encoding the rarer IL-1R1 protein, they saw it pop up, at varying levels, among all 19 solid-tumor cancer types.
ATLAS worked. Planet failed.
T cells that show up in great numbers in head and neck tumors, but not in similar tissues of the mouth inflamed by common ailments such as gum disease.
It seems that this odd group of T cells have mixed up their highly specialized assignments within our immune systems and are now working to protect tumor cells.
If DTIL can unsteath cancer cells before treating pts with stealth T cells from donors, ORR will be a lot higher. No need for neoantigens
ADXS called that HOT. It turned out to be ice as neoantigens are like fingerprints
Is 'personalized allogeneic' oxymoron?
Cell therapy will be the backbone of therapies to treat solid tumors.
Roche is testing a mechanism that blocks TIGIT, a receptor capable of shrouding cancer cells from the immune system. Its drug, tiragolumab, binds to the receptor, preventing its deception. Roche added the new drug to its blockbuster medicine Tecentriq in patients with a form of lung cancer.
But during an interim analysis, Roche's regimen failed to meet the study's two key goals. It didn't have a statistically significant impact on the length of time before patients worsened — a measure known as progression-free survival. And it didn't improve overall survival.
https://www.investors.com/news/technology/biotech-stocks-arcus-and-others-hammered-on-roche-flop-in-lung-cancer/?src=A00220
NVS should buy DTIL with their stockpile of peanuts.
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-?
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.
No bad news after 12% sell down?
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 LD mentioned in YTB323 P1 protocol
https://clinicaltrials.gov/ct2/show/NCT03960840?term=YTB323&draw=2&rank=1
DTIC seems to be the only one increasing conditioning chemotherapy.
These data demonstrate the potential advantages of combining iPSC-derived CD38-null NK cells with anti-CD38 antibodies as a novel therapeutic strategy for reducing conditioning chemotherapy, depleting alloreactive lymphocytes, and promoting off-the-shelf cell therapy.
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
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.
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.
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.
Biotechs are filled with frauds. Investors kept in the dark until the well runs dry.
CEO knew Planet failed when DP was made for cohort A.
NPT turned out to be a lost TIL. 10000 pg promised, 1000 pg IFN actual
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.
DTIL is a bargain?
young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978753/#SD1
Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-021-02006-4
Intratumoral CD40 or CD47 + ACT after HD lymphodepletion to treat solid cancers should be tried. Elevated MCP-1 is tied to higher ORR in CAR T trials.
Is HD lymphodepletion used in any NK cell therapy trial?
Intratumoral CD40 agonist sotigalimab with pembrolizumab induces broad innate and adaptive immune activation in local and distant tumors
There was a robust upregulation of T cells, macrophages, CD8+ T cells, and cytotoxic gene signatures in responders. Additionally, responders had an increase in Th1 gene signatures; an increase in TGF-ß1 gene expression was also noted. In distant lesions, the same gene signatures were upregulated.
https://acir.org/weekly-digests/2022/april/aacr-annual-meeting-2022#therapies
Mellman described published work linking PD-1 and CD28 signaling through the phosphatase Shp2. Evidence also showed that myeloid cells, particularly dendritic cells in the TME, were the critical source of PD-L1 ligand.
https://acir.org/weekly-digests/2022/april/aacr-annual-meeting-2022#therapies