Fate Therapeutics Inc (FATE) News

NK is fine for SLE since the depletion of the memory B cells is the goal. For solid, creating polyclonal T cells with memory phenotype is the key for OR duration.
From ChatGPT:
Studies with 1XX CAR T cells highlight their enhanced capacity for cytokine production and survival, suggesting a stronger potential for interaction with and modulation of DCs compared to conventional CAR T cells. Dendritic cells in the TME can process these antigens and cross-prime endogenous T cells against TAAs, creating a polyclonal immune response that complements the CAR T-cell activity.

They should get a B7-H3 CAR into the clinic https://www.oncologypipeline.com/apexonco/fourth-challenger-dualitybio-and-biontech

Based on preclinical data targeting the IgC domain is more effective https://www.nature.com/articles/s41467-023-41631-w

Unlike NKs, the differentiation of T-cells from iPSCs is (far) more complex. Also, the NKs from iPSCs are more comparable functionality to PB/CB NKs, and can kill independent from the CAR.

It would make sense to test the two https://aacrjournals.org/cancerimmunolres/article/7/3/363/469550/NK-Cells-Expressing-a-Chimeric-Activating-Receptor

But there are still hurdlers (for the NKs) to overcome, including persistence and lack of expansion. The use of an IL15-RF may impair NK functions as well https://insight.jci.org/articles/view/96219 https://www.pnas.org/doi/10.1073/pnas.1012128107

1xx, autologous T cells and lactate
https://pmc.ncbi.nlm.nih.gov/articles/PMC11588660/

SP from 100 to 1 while revamped pipeline from 1 to 100

CEO was pretty bullish on 825 + cetuximab. I think Ig1 is as effective as TCE as it activates the innate arm.

FT825 would require an additional receptor https://ashpublications.org/blood/article/140/Supplement%201/7429/491146/A-CD3-Fusion-Receptor-CD3-FR-Uniquely-Enables

Failure to revive old cells
https://www.merck.com/news/merck-provides-update-on-keyvibe-and-keyform-clinical-development-programs-evaluating-investigational-vibostolimab-and-favezelimab-fixed-dose-combinations-with-pembrolizumab/

FATE revamped it's cell to deal with TME. Yet the SP is 1.8% of what it used to be. 95% investors were in it for ride because J&J was on board. They had little understanding of science.

Why bother with CARNK after they licensed 1xx from MSK. CAR T 1xx lowers the activation and energy req'd to survive in the hypoxic TME. More durable and lower CRS CART therapy will beat ADC in terms of AE and OS long term.

Hard to say. After the termination of a 2020 collaboration agreement with Johnson & Johnson's subsidiary Janssen, FATE slashed its pipeline, including FT536, FT516, FT596 and FT538.

The combination of p95HER2.CAR T cells and HER2?x?CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models
https://pmc.ncbi.nlm.nih.gov/articles/PMC11574131/

So they abandoned FT536 after looking at PK in 6 pts.

I am looking for some FT536 P1 data to figure out why they decided on 3 day dosing at U of M?

Either based on data from other trials and/or the biology of NKs (they do not typically expand upon encounter with antigen and lack long-term persistence). It looks to be a compressed dosing schedule, which could extend exposure and increase Cmax levels.

That poster only listed 3 pts dosed at 100M cells mono, how about higher dosages?

Monotherapy escalation was continuing at 300 million cells/dose. So I assume (rightly or wrongly) that those two patients had been treated at this dose level. From memory, they were going to test at least a third dose level as well (500 million cells/dose). Also, had an option to add IL-2 once the MTD had been reached.

I am looking for some FT536 P1 data to figure out why they decided on 3 day dosing at U of M? That poster only listed 3 pts dosed at 100M cells mono, how about higher dosages?

They presented initial data at SITC '22 (another two were enrolled before it was terminated) https://fatetherapeutics.com/wp-content/uploads/2022/11/SITC2022_FT536_FinalDraft-VFINAL.pdf

Another trial (not sponsored by FATE) is ongoing https://clinicaltrials.gov/study/NCT06342986

A number of biotechs were hit (hard) this week.

Have you seen the clinical data from FT536 P1?

What is the hidden message that caused the selloff?

2025 is the year of 1xx. HER2 ADC sales is $5B. 825 + cetuximab beats ADCs

The news https://www.globenewswire.com/news-release/2024/12/09/2994080/24675/en/Fate-Therapeutics-Presents-New-Phase-1-Clinical-Data-of-FT819-Off-the-shelf-CAR-T-cell-Product-Candidate-for-Systemic-Lupus-Erythematosus.html

Hopefully, another (small) pop tomorrow based on the latest news.

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

"Different subsets are important for activity"
I think that just reflect the ever changing immune makeup as body reacts to new and existing stimulus. Just like macrophages that are not 100% M1 or M2.

For oncology, it will be put on the back burner.

Turns out a few companies screened a CAR panel, including CD3 family, ITAM silent, etc. So it could be possible. As for gd-T cells, results from one group indicated that igd-T cells have differences when compared to PB-derived gd-T cells https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(23)00057-7

Different subsets are important for activity https://www.nature.com/articles/s41586-022-05593-1

Improved Memory Phenotypes: The reduced stress allows a greater proportion of 1XX CAR T cells to retain central memory and effector memory phenotypes, which are crucial for long-term persistence and functionality.
Lower Cytokine Production: By producing cytokines at more moderate levels, 1XX CAR T cells avoid the excessive metabolic demands and inflammatory feedback loops that can lead to early cell death or dysfunction.
the higher stress in CAR T cells can make them more susceptible to NK cell-mediated clearance.

New CEO before ASH. PhD likes CAR T with 1xx.

Other ipsc bios can't use 1xx
"We have exclusively licensed from MSKCC foundational intellectual property covering iPSC-derived cellular immunotherapy, including T-cells and
NK cells derived from iPSCs engineered with CARs, for human therapeutic use. We have also licensed from MSKCC intellectual property covering
compositions of novel CAR constructs, including the use of a novel 1XX co-stimulatory domain, and of genetically engineered CAR T-cells, including
methods of making these cells using CRISPR for certain targeted gene modifications."

Dr. Huntington is the CSO. From this https://acir.org/weekly-digests/2024/november/sitc-39th-annual-meeting-2024#2

''A 2008 NCI survey identified IL-15 as one of the top cytokines for potential immunotherapy, and multiple subsequent studies have demonstrated a critical role for IL-15 in multiple immune cell types. Further, direct and correlative data have linked IL-15 to good outcomes in animals and humans. Nonetheless, IL-15R agonists have failed in the clinic due to severe toxicity.

Spurred on by this challenge, Nicholas Huntington focused on how to target the signaling-induced inhibitory pathway, reasoning that although IL-15R is widespread throughout the body, IL-15 levels are very low in healthy tissue (but high in tumors) and that by preventing receptor degradation, cells would be hyperresponsive to the IL-15 produced in the tumor and not activated systemically. A CRISPR knockout screen in human NK cells under conditions of low IL-15 identified a number of genes (UBE2F, ARIH2, CISH, CUL5, RNF7, DCUN1D3, UBE2L3, ELOC), whose elimination allowed better NK cell growth.

All these genes were involved in protein homeostasis affecting neddylation and subsequent ubiquitination, leading to degradation. Functionally validating these results, individual knockouts of these genes in NK cells and the NK-92 cell line enhanced proliferation, cytokine production, and metabolic features of the NK cells, and the expected upregulation of IL-15R surface detection. Importantly, an inhibitor of pan-neddylation phenocopied the effects of UBE2F-gene knockouts, supporting that the pathway could be targeted for therapy.

Serial cytotoxicity studies with gene knockouts in NK cells or CAR NK cells demonstrated robust serial killing, indicating the cells were metabolically very fit and resistant to exhaustion, which translated to enhanced control of MHC-I-expressing or -deficient tumors in syngeneic mouse models. The unexpected observation of activity against MHC-I-expressing tumors was a direct effect of CD8+ T cells, but enhanced by hyperactive NK-mediated improvements to the T cell response. Most of the identified gene targets were part of a degradative pathway; some could be deleted with minimal effects, and so were non-essential. Importantly, some of these targets were enzymes, setting up the opportunity to identify small molecular inhibitors specific to this class of drug targets.''

A number of companies have licensed it. Based on new data is seems that there is no one-size-fits-all, so pooled screening of different CARs to try and find the best for specific types will be needed https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(23)00495-1

Can they license CAR 1xx from MSK?

3 pts remain on study. No relapse. Sounds like a telegraph?

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

A post on LinkedIn (by Alex Shih-Min Huang who is VP, Head of Cell Therapy at BGNE): ''Though our very first experiment was initiated only 2.5 years ago amidst ongoing laboratory construction and pandemic, fast forward to this day, we have already 1) generated a proprietary, well-characterized GMP grade iPSC clone collection designated for our future gd T and ab T cellular products, 2) established our unique efficient, enrichment-free, feeder-free methodologies that deliver impressively high purity and high expansion fold for our iPSC derived gd T and iPSC derived CD8 ab T platforms, and 3) engineered proprietary genetic elements that further enhance the longevity and potential efficacy of our effector cell populations. Our platforms are designed to allow plug-and-play for a variety of CAR-T and TCR-T cell therapies with potential to address unmet needs in diverse indications.''

One for FT819 as well https://www.globenewswire.com/news-release/2024/11/18/2982757/24675/en/Fate-Therapeutics-Presents-6-Month-Follow-up-Data-on-First-Patient-Treated-in-Phase-1-Autoimmunity-Study-with-Fludarabine-free-Conditioning-and-FT819-Off-the-shelf-1XX-CAR-T-cell-P.html

The PR https://www.globenewswire.com/news-release/2024/11/18/2982736/24675/en/Fate-Therapeutics-Highlights-FT522-Off-the-shelf-ADR-armed-CAR-NK-Cell-Product-Candidate-at-2024-ACR-Convergence.html

They need to pick up the pace of enrolment. If they don't see activity at DL2, I think it could be in trouble.

Big volume into the close, over 12 million. Someone knows something.

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

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

Here is the bar for the FT825 + Ab bar:

Intervention: Enhertu vs. physician’s choice of standard chemotherapy.
Key Outcomes:
Progression-Free Survival (PFS):
Median PFS with Enhertu: 9.9 months.
Median PFS with chemotherapy: 5.1 months.
A 50% improvement.

$5B HER2 ADC sales 2023

3 fold increase in dosage leads to 20 fold increase in copies*day/µgDNA.
The potential for FT522 dose-dependent activity was supported by pharmacokinetics (PK), which showed a greater than 20-fold increase in median cumulative PK between the two dose levels (>80,000 copies*day/µgDNA for A-DL2 and

Based on SLE data, FATE should try CY + 522 + rituximab, which would suppress neutrophil count and up T cells plus innate activation.

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

Not only for that, but there is evidence that it could modulate the TME (promote M1 polarisation of macrophages and/or reduce stromal density) and upregulate CXCL8 (CXCR2 is its ligand), which could increase trafficking.

Looks like Shoreline has pivoted (yet again) to autoimmune https://themalaysianreserve.com/2024/11/16/shoreline-biosciences-to-present-at-2024-stifel-healthcare-conference/

In vivo now (for some reason) https://www.biorxiv.org/content/10.1101/2024.11.06.621821v1.full

Hopefully, they will use their iPSC platform to test it.

They are working on at least three cell therapies, two of which are auto CAR-T's. For the first, they will utilise their knock-in/knock-out protocol to introduce the CAR and gene modification(s) precisely at the TRAC locus to generate four anti-HER2 CARs: PRODH2 OE [1], PRDM1 KO [2], PRODH2 OE plus PRDM1 KO, and control. If successful, this study will identify the best performing and provide sufficient data to support a path towards an IND.

The second CAR will target ENPP3 (data from another group [3]). Again, they will utilise their knock-in/knock-out protocol to introduce the CAR and gene modification(s) precisely at the TRAC locus to generate four anti-ENPP3 CARs: CTLA-4 tail fusion [4], PRDM1 KO, CTLA-4 tail fusion plus PRDM1 KO, and control. If successful, this study will identify the best performing and provide sufficient data to support a path towards an IND.

Refs:
1 https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00053-5
2 https://www.nature.com/articles/s41587-022-01639-x
3 https://aacrjournals.org/clincancerres/article/22/8/1989/265987/AGS16F-Is-a-Novel-Antibody-Drug-Conjugate-Directed
4 https://www.nature.com/articles/s41590-023-01571-5

Yes. nab-paclitaxel is myleosuppressive to lower neutrophil counts and NET.
It will be interesting to see how ADR works in BCL where neutrophil plays secondary role.