Fate Therapeutics Inc (FATE) Options

I will, but I don't see auto CAR-T's being feasible for the largest and most lucrative parts of the market.

CABA CEO talk at Cowen is worth a listen. ICANS caused by T cell clones, AUTO efficacy, logistics bottleneck .........

Studies suggest that 5-20% of DLBCL cases may have CD19-negative malignant cells at baseline, and CD19 loss can increase due to treatment pressure. That explains why auto CART had higher ORR and PFS. AUTO is TIL with 50% CD19 CAR and 50% without. I think 819 360 M will be good without CY since Treg is lacking in SLE patients who have no malignant cells.

SLE and CART
https://pmc.ncbi.nlm.nih.gov/articles/PMC11694027/#B181

CEO said they have submitted a series of abstracts to EULAR.

I meant 825

819 is turning into mAb conjugated to a mutated T cells. ATC. Muti dose, muti cycles is big deal.

819 did demonstrate durable B-cell depletion for at least one month post treatment (in the presence of flu-free conditioning). They will escalate to DL2 (at 720M cells) as well.

The CEO said at one of the conferences.

Possibly. Or (early) 2026. I know the CEO said there appears to be light at the end of the tunnel and how they are progressing ahead for a pivotal strategy.

819 Pivotal by 2025 year end

819 update at EULAR. Hard to believe they didn't see confirmation data in other 2 patients before adding 10 more pts at 360 mi. cell dose

FATE, new 52 week low

Data update for FT819 at EULAR Congress? How you found out?

Yes. A lot of patients harbor both HCV and HBV. HPV-driven cancers (cervical, throat) have the highest MIC-A/B expression, making them ideal for MIC-A/B-based immunotherapies.
Do you think 525 + Rituximab will be more potent since LD is not used?

Data update for FT819 at EULAR Congress, in June. A more comprehensive update at ACR, in late October. We could see an update for FT825 at SITC (in Nov) and for FT522 at ASH (in Dec).

HCV is pretty much curative (90-95%+). As for HBV, bepirovirsen* looks promising and there are a number of other therapies in development, including epigenetic and genetic editing.

* https://www.nejm.org/doi/full/10.1056/NEJMoa2210027

FT836 for HBV/HCV patients?
Depletion of infected and cancer cells in 1 shot. HCV therapy cost $50K and has no impact on HBV.
CXCL8 levels correlate with HCV viral load—higher expression is seen in chronic HCV infections.

This is why 1xx CAR matters. CD19 donor dose effective at 26 mil per MSK trial
$FATE 1xx: recommended phase 2 dose (RP2D) was 1 × 106 CAR T cells/kg.
$ALLO 120× 106 CAR T cells

https://ashpublications.org/blood/article/142/Supplement%201/892/502952/A-Phase-I-Study-of-CD19-Targeted-19-T2-28z1xx-CAR

For in vivo, I know a number are using either viral vectors or LNPs to target certain populations, such as CD7+ T and NK cells.

As for the TME, CAR-T can actually make it worse. In this paper (looking a B-ALL), MDSCs expand, hypoxia increases, and T-cells (both CAR and endogenous) exhibit severe exhaustion. So multiplex gene editing (including designing local secretion of certain ''payloads'') and combinations will likely be needed https://www.biorxiv.org/content/10.1101/2024.12.20.629119v1.full

For cancer, I hope they open dose expansion cohorts testing FT836 with (low dose) radiotherapy [1], (low dose) chemo [2], or panobinostat [3]. Also, test multiple infusions.

Refs:
1 https://aacrjournals.org/cancerres/article/81/13_Supplement/1591/667388/Abstract-1591-FT536-Preclinical-development-of-a
2 https://jitc.bmj.com/content/10/Suppl_2/A291
3 https://pmc.ncbi.nlm.nih.gov/articles/PMC7269842/

Holy grail: pan cancer, off the shelf, no chemo T cells. all that for a donut.
How many bio investors can read?

Revealing .. T-Dxd and EGFR mut, KRAS ....

There is a lot to be digested in the new deck. The tumors targeted are reviewing.

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

ADR works like CD16a/ADCC but targets exhausted T cells 4-1BB+ instead. Invivo has plenty of issues uptake, off target...... Effective ACT needs to keep TME from resurgence after LD. FT525 have a good chance of doing it with 3 doses.

New deck https://ir.fatetherapeutics.com/static-files/1cac8c4b-ac0b-42cf-bc22-80acbc38405b

FT829 (anti-CD19/CD38) is new and will be tested in autoimmune diseases. CD38 is involved in many, including lupus https://www.sciencedirect.com/science/article/abs/pii/S156899722300023X

I hope the anti-CD19/BCMA candidate is not far behind and they will take at least another forward (anti-CD19/CD20).

A lot rests on the ADR tech.

I should also say that in vivo cell therapies are moving into the clinic (some are not giving any LD chemo). Pretty early data from one trial https://jitc.bmj.com/content/12/Suppl_3/A1712

FT829, FT836 no LD req'd. FT525 DBLCL no LD req'd. CEO is sending a message but few can hear.

Would be clear if they stratified by NLR. Gastric have higher NLR where the Ab failed for good. It seems to work when NLR is low (before VEGF) with high CD8 clones in CRC.

Many failed attempts 4-1BB (26 clinical prgms - 0 approved), these T cells must be passively protecting the cancer cells. Also Circulating aged neutrophils (e.g., those undergoing senescence or prolonged circulation due to impaired clearance) have been reported to express higher levels of 4-1BB compared to younger neutrophils.
We will see if high dose 522 + Rituximab can result in CR without LD in DBLCL patients.

The PR is an utter mess! The ORR across subgroups is higher, but the (m)PFS isn't that great.

We won't know until it is tested, but from this: ''We found activated CD19 CAR.ADR T cells have lower levels of detectable 4-1BB on their surface compared to CD19 CAR T cells, suggesting partial downregulation or masking of 4-1BB upon ADR expression (Supplementary Fig. 9a). Indeed, expression of a truncated non-signaling ADR on activated T cells protected them from cytotoxicity by ADR T cells (Supplementary Fig. 9b-d) so that cis-masking of 4-1BB by ADR likely contributes to fratricide resistance of activated ADR T cells.'' https://pmc.ncbi.nlm.nih.gov/articles/PMC7854790/

FATE has its own data (that they still won't share!)

Hidden message from LPTX on CRC
No prior anti-VEGF therapy: Patients in the Experimental Arm (n=49) had an ORR of 51%, compared to 29% ORR in the Control Arm (n=45)
Prior anti-EGFR therapy: Patients in the Experimental Arm (n=28) had an ORR of 54%, compared to 27% ORR in the Control Arm (n=22)

To be deleted by ADR?
Exhausted T cells, typically arising from chronic antigen stimulation in the tumor microenvironment (TME), may express activation-induced costimulatory receptors like 4-1BB alongside inhibitory receptors
exhausted T cells are not actively immunosuppressive like Tregs. Their role is more of a failure to sustain effective anti-tumor responses rather than actively suppressing other immune cells. However, their presence in large numbers can create a functionally "tolerant" immune environment that indirectly benefits the tumor.

The key to success is CXCR2 and 1xx for FATE CART. MSK 1xx CD19 auto trial showed ORR at 25M cells dose, so trogocytosis, persistence and proliferation must be optimal to be effective.

One of the potential downsides of inhibiting (CD16(a)) shedding is that it could slow NK detachment and reduce serial killing https://rupress.org/jcb/article/217/9/3267/120862/Shedding-of-CD16-disassembles-the-NK-cell-immune

It was shown some years ago that CD64 binds to the same IgGs, but with at least 2-3 orders of magnitude higher affinity than CD16(a). Based on that data, I think they should switch to using it and look to add additional modifications https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01455-z

They (and others) need to learn from the (early) mistakes of FATE.

Trogocytosis can impact both CAR-T, as well as CAR-NK therapies. Strategies to overcome trogocytosis-induced antigen loss, fratricide and/or cell exhaustion include, pharmacological targeting, modulating CAR affinity, ''armouring,'' modulating the signalling domain(s), or using a dual CAR strategy. Some preclinical data on the latter https://www.nature.com/articles/s41591-022-02003-x

The functional effects of trogocytosis remain to be elucidated, however, it has been shown to interfere with successful CAR-mediated antitumor responses as it promotes tumor antigen escape as well as CAR T cell dysfunction due to fratricide killing
https://jitc.bmj.com/content/11/2/e005691

This study was done without ADCC.

expression of CXCR2 in CAR-T cells can significantly improve these T cell migrating to the tumor microenvironment of hepatocellular carcinoma, which provides the strong evidence to support that CXCR2 is of great potential to be utilized in CAR-T cell therapies for various solid tumors.

https://onlinelibrary.wiley.com/doi/full/10.1002/eji.201948457?utm_source=chatgpt.com

Both follow LD chemo in Cycle 1 (each cycle is approximately 61 days). Based on the safety, tolerability, and radiographically confirmed clinical benefit to treatment (in Cycle 1), participants may be considered for an additional treatment cycle (Cycle 2 retreatment).

NEUK201-00* is being tested in advanced/metastatic solid tumours at a single site.



* It could be an iNK with just a high-affinity non-cleavable CD16(a) receptor, but this comes from a Chinese site that has undergone translation. The IL-2 dose is intermediate.

ADCC will lead to higher expression of CXCL8 by innate cells which will lead to more FT825 into TME. The combo trial will be a game changer. What is the dosing schedule for cetuximab?

Translational data from the PhI B-cell lymphomas trial demonstrated primary, secondary and tertiary tissue trafficking and clearance of CD19+ cells. That should help enable an immune reset in autoimmune diseases.

The next-gen CAR-T's will incorporate a suite of novel synthetic edits that are designed to enhance homing and biodistribution to secondary and tertiary tissues.

I hope they will pick up the pace with enrolment. It can't be as slow as last year.

Shoreline has let go of an undisclosed number of employees tied to a cell therapy project with GILD's Kite Pharma, Endpoints News reported. Shoreline CEO declined to disclose the number of workers that were laid off and said the future of the collaboration is still ''to be determined.''

The two had agreed to change the focus of their partnership. Instead of developing a CAR-iNK cell therapy for B-cell lymphomas (either CD19-targeted or CD19/CD20-targeted), they switched to autoimmune diseases. Shoreline already had a pre-IND meeting with the FDA and was recruiting US and international clinical trial sites for a PhI trial in autoimmune diseases. They were going to enter the clinic in the coming months and planned to give Kite the possibility of opting in after concluding the trial.

As Kite went through leadership changes in recent years, Shoreline's CEO said the two had a ''wonderful collaboration,'' including being aligned with the new [autoimmune] focus for that therapy. They agreed on ''90%'' of the terms in an adjusted deal, including another potential equity investment from GILD, but they couldn't come to an agreement on any ''back-end economics.'' Shoreline believed it deserved a ''larger portion on [the] upside.''

Pipe valued at 10% of paid in capital. A CART that follows the chemotactic gradient to TME is free today.

Ft825 - 4 more sites added

FT819 can act as a ligand sink and change DC/CD8, NLR ratios in 2nd lymphoid and inflammed tissues. Creating a new Bronx so to speak.

CXCR4 is critical for the organization of secondary lymphoid tissues, such as lymph nodes and spleen, where immune responses are initiated.
Dysregulation of CXCR4 signaling may contribute to abnormal germinal center reactions and the development of autoreactive immune cells.