Lyell Immunopharma Inc (LYEL)

[glenn1919]

LYEL.....................................https://stockcharts.com/h-sc/ui?s=LYEL&p=W&b=5&g=0&id=p86431144783

[Monksdream]

LYEL active in the Gaucho session

[jondoeuk]

Tempting but I will remain on the sidelines.

[Monksdream]

LYEL under $3

[glenn1919]

LYEL..................................https://stockcharts.com/h-sc/ui?s=LYEL&p=W&b=5&g=0&id=p86431144783

[jondoeuk]

They could be working on this https://ash.confex.com/ash/2023/webprogram/Paper182417.html

[jondoeuk]

Upcoming https://www.globenewswire.com/news-release/2023/09/27/2750444/0/en/Lyell-Immunopharma-Announces-the-Acceptance-of-Six-Abstracts-for-Presentation-at-2023-Society-for-Immunotherapy-of-Cancer-SITC-Annual-Meeting.html

[Monksdream]

LYEL new 52 week low

[jondoeuk]

LYL119 https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=13739

[jondoeuk]

Preclinical data from another group (LYL119 will be NR4A3-deficient) https://www.biorxiv.org/content/10.1101/2023.04.21.537841v1.full

[glenn1919]

LYEL..........................https://stockcharts.com/h-sc/ui?s=LYEL&p=W&b=5&g=0&id=p86431144783

[jondoeuk]

The FDA has cleared an IND for LYL845. The PhI trial will initially enroll patients with relapsed and/or refractory metastatic or locally advanced melanoma and subsequently expand into NSCLC and CRC. Initial data presentation is expected in 2024.

[jondoeuk]

SITC titles

NR4A3 gene editing and c-Jun overexpression synergize to limit exhaustion and enhance functional activity of ROR1 CAR T cells in vitro and in vivo

Engineering potent CAR T-cell therapies by controlling T-cell activation signaling parameters using the Stim-R™ technology, a programmable synthetic cell-signaling platform

The Epi-R™ technology produces a polyclonal TIL product (LYL845) with diverse tumor-reactive clones that have stem-like qualities and anti-tumor function

The Epi-R™ technology produces a polyclonal TIL product (LYL845) with a greater expansion success rate across hot and cold tumors, improved product phenotype, and maintenance of TCR diversity

Increased potency and functional persistence in vitro of a next-generation NY-ESO-1-specific TCR therapy incorporating Gen-R™ genetic reprogramming technology

[NY1972]

recent technical advances using culture conditions with IL-7/IL-15 and
the addition of IL-21 may enhance the enrichment for TSCM cells
in the final CART product (74–76), which can be further increased
with the addition of drugs blocking T-cell differentiation, such as
glycogen synthase-3 inhibitors (77). Nevertheless, robust clinical grade protocols for generating TSCM-enriched CART products
have not been developed so far. Recently, a few CART19 clinical
trials for DLBCL have been conducted in which CART products
were manufactured from CD62L+ isolated T cells to generate
cellular products enriched for TCM cells (21, 78); however, due to
prolonged culture conditions, enrichment for TSCM and TCM
subsets in the infused product could not be demonstrated

https://www.frontiersin.org/articles/10.3389/fimmu.2022.904497/full

[jondoeuk]

The AEs from the LD chemo*. I expect more data (dose expansion is ongoing) from them at ASH. As for NVS, a pivotal trial is planned and DL2 (12.5M) is the recommended dose.

* Some very early clinical data testing an anti-GD2 CAR-T with constitutive signaling from an engineered IL-7 receptor

[NY1972]

Thanks for the link.
Most commonly reported grade 3/4 AEs were neutrophil count decrease (6/9, 67%), anemia (5/9, 56%), thrombocytopenia (2/9,22%), platelet count decrease (2/9, 22%) and no infection was reported. Complete response rate(CRR) was 78%

Compared to T-Charge
http://www.koreabiomed.com/news/articleView.html?idxno=12767

[jondoeuk]

For Epi-R, they use media with high concentrations of potassium (as well as multiple cytokines). As for that, T-Charge or BE, I think a product with mostly ''stem-like'' cells and additional edits will be needed. But it doesn't have to be the latter, as shRNA can be used. Here are some clinical data on an anti-CD19 CAR-T with knock-down of both PD-1 and TIGIT https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.7522

[NY1972]

Which will perform better ? BE with 7,8 edits on many genes, Epi secret sauce
or T-Charge which seems to add a CAR only to starting material in order to retain CD4/CD8 ratio.
YTB323 CAR-T cell products generated via this novel expansionless manufacturing process retained the immunophenotype of the input leukapheresis materia

[jondoeuk]

That depends. Typically, the more the cells expand during manufacturing, the more they differentiate. In the case of ALLO, it seems most are effector memory (manufacturing time is ~19 days and there are a number of steps involved). LYEL refer to this as the expansion/quality paradox. With Epi-R, they have shown they can expand TCR-T cells up to 18 billion by day ten. In addition, these cells are over 94% viable and maintain their ''stem-like'' qualities.

[NY1972]

Do you need Epigenetic Reprogramming if pts can be treated with healthy, young donor T cells?

[jondoeuk]

ISSCR poster https://ir.lyell.com/static-files/971404cb-28eb-46fc-839f-b20735899373

[jondoeuk]

Posters https://ir.lyell.com/static-files/d3a3d05c-1b39-4092-bf82-a486933bc268

https://ir.lyell.com/static-files/6014be8d-4e9d-499b-a496-513d2962f3e4

[jondoeuk]

1115: Epigenetic Reprogramming (Epi-R™) Yields T-Cell Receptor Products with Improved Stemness, Metabolic Fitness, and Functional Activity in the Presence of Persistent Antigen Exposure https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=2014

661: Preclinical Development of LYL797, a ROR1-Targeted CAR T-Cell Therapy Enhanced with Genetic and Epigenetic Reprogramming for Solid Tumors https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1597

[jondoeuk]

GSK has updated the master protocol for their next generation constructs to include a third arm with GSK4427296 https://clinicaltrials.gov/ct2/show/NCT04526509

This uses Epi-R.

[jondoeuk]

AACR poster https://ir.lyell.com/static-files/ad2cd8dc-b41b-4536-a854-c4d1246422e6

[jondoeuk]

The PhI (n=54) of LYL797 has now been listed. The dose-escalation phase (TNBC only) will investigate four dose levels to determine the recommended RP2D. The dose expansion will enroll both TNBC and NSCLC.

[jondoeuk]

A new review https://www.sciencedirect.com/science/article/pii/S0952791521001278

[jondoeuk]

Morgan Stanley webcast https://morganstanley.webcasts.com/viewer/event.jsp?ei=1488969&tp_key=3cedc4a917

[jondoeuk]

New deck https://ir.lyell.com/static-files/96379999-4d8e-466b-a5d5-44f5f6f88583