[jondoeuk]

True, but FATE has been moving a lot of the tech, including the CD64 receptor at a snails pace with some of the first data on that being shared by them almost five years ago!

[jondoeuk]

FATE has presented preclinical data on an MR1-restricted TCR in the past.

MR1 is monomorphic unlike HLA Class I and II alleles (targeting the MR1-ligand enables treatment across all HLA-types).

HLA LOH is a mechanism of escape across different types of cancer (homozygosity reduces the likelihood of MR1 loss).

Metabolites presented by MR1 are immutable, unlike specific peptide sequences (reduced scope for mutation to drive antigenic loss).

Cancer-specific MR1 T-cells are active against solid tumours and haematological malignancies (potential for treating many types of cancer).

See https://www.nature.com/articles/s41590-019-0578-8 and https://www.sciencedirect.com/science/article/abs/pii/S0952791520301461

[jondoeuk]

A new preclinical paper (iT CD8+ ab cells engineered with a CAR, TCR, and hnCD16 receptor) https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00268-X

[NY1972]

TCE still expected to be the go to drug for SLE.. collective wisdom says durable B cells aplasia is the key to success for AID. Many worry about over activation, not T cell exhaustion after treatments. I guess rheumatologists never worry about cancer, they just let oncologists take over the pts.

[jondoeuk]

I don't view the data to date of TCEs as encouraging.

[NY1972]

$FATE 819 v. TCE
POS0057 (2025)
EFFECTS OF T CELL ENGAGERS TREATMENT ON B AND T CELLS
IN AUTOIMMUNE DISEASE
after the first cycle of blinatumomab and after completion of teclistamab step up dosing,
we observed an accumulation of PD1+ exhausted CD8 T cells (blinatumomab: from 11.2± 5.8% to 20.7 ± 4.1%;
teclistamab: from 6.9± 6.6% to 24.3± 9.2%). In addition, Teclistamab therapy lead to an increase in CD62L
CD45RA CD8 effector memory (EM) and CD62L CD8 effector memory re-expressing CD45RA (EMRA) T
cells. CD8 TEM and TEMRA also expressed more PD-1 compared to the other CD8 subpopulations, suggesting
increased exhaustion (Figure 2). An increase in CD8 TEM was also observed after the first cycle of
blinatumomab therapy.
+ -
after the first cycle of blinatumomab and after completion of teclistamab step up dosing,
we observed an accumulation of PD1+ exhausted CD8 T cells (blinatumomab: from 11.2± 5.8% to 20.7 ± 4.1%;
teclistamab: from 6.9± 6.6% to 24.3± 9.2%). In addition, Teclistamab therapy lead to an increase in CD62L
CD45RA CD8 effector memory (EM) and CD62L CD8 effector memory re-expressing CD45RA (EMRA) T
cells. CD8 TEM and TEMRA also expressed more PD-1 compared to the other CD8 subpopulations, suggesting
increased exhaustion (Figure 2). An increase in CD8 TEM was also observed after the first cycle of
blinatumomab therapy.
40% level of PD-1? exhausted CD8? T cells after blinatumomab in an SLE patient is a red flag for markedly impaired immune surveillance. If B cells recover (as they usually do after blina wears off), the risk of EBV-driven BCL or LPD is significantly increased

[NY1972]

ARID5B can make NK great again. Professors work so slow so FATE may not have the cash to wait it out unless FT819 is approved for SLE.

[jondoeuk]

No, but they do have a research collaboration with the University of Minnesota led by Dr. Miller, who was a co-author of the ARID5B paper and will play a role in the FT596 trial.

Research by his lab lead to the creation of a FcyR fusion CD64/16A receptor, consisting of the extracellular region of CD64 and the transmembrane and cytoplasmic regions from CD16A. It has been exclusively licensed to FATE. CD64 is expressed by monocytes and macrophages, but not NKs, with 30-100 fold higher affinity for IgGs than CD16A.

An important feature of this fusion receptor is that due to its high affinity state, soluble mAbs can be pre-adsorbed to (CAR-)iNKs that express it, and these pre-absorbed mAbs can be switched or mixed.

They have also tested the fusion receptor with the transmembrane regions of CD16A or NKG2D and signaling/co-signaling domain from CD28, 2B4, 4-1BB, and CD3z.

[NY1972]

FT596 is not even included in their pipe.

[jondoeuk]

The University of Minnesota has funding to test FT596 (an anti-CD19 CAR-NK with mb15/IL-15Ra fusion and a hnCD16 receptor) plus rituximab (anti-CD20 mAb) as maintenance therapy to see if this limit relapse after an autologous HCT in patients with lymphoma. This trial is FDA-approved and will first establish an MTD at day +30 after engraftment and then, if single dosing is safe, move to day +7 before engraftment with the goal of three doses in the first hundred days.

They will also test enhancements of FT596 cell metabolic fitness by ARID5B overexpression and/or CD38 knockout. FATE has already published data on the latter, but here is data on the former https://rupress.org/jem/article/215/9/2379/124250/ARID5B-regulates-metabolic-programming-in-human

[jondoeuk]

A thread

Excited to share our Cancer Cell @CellPressNews article on the discovery of the IL-15 Receptor "Regulome". A technical tour-de-force from the Immunology, computational biology & functional genomics teams @oNKo_innate @MonashBDI https://t.co/EXL6lCkJfu

— Nicholas Huntington (@Dr_Nick_Bikes) June 13, 2025

[jondoeuk]

One is developing both. They have an auto anti-GPC3 CAR-T in the clinic and it secretes a bi-specific mAb (VHH-ScFv), which targets CD39 (an enzyme crucial for converting extracellular ATP into adenosine) and PD-L1. Human data https://meetings.asco.org/abstracts-presentations/253038

Another (again, targeting GPC3) will secrete a TCR-mimic mAb targeting AFP https://www.researchgate.net/publication/375152905_241_Dual_targeting_liver_cancer_by_GPC3_CAR-T_cells_secreting_a_bispecific_T_cell_engager_antibody_for_an_intracellular_tumor_antigen_AFP

[jondoeuk]

New (FT819) update https://www.globenewswire.com/news-release/2025/06/11/3097578/24675/en/Fate-Therapeutics-Announces-Updated-Clinical-Data-for-FT819-Off-the-shelf-CAR-T-cell-Product-Candidate-Demonstrating-Durability-of-Drug-free-Remission-for-Severe-Lupus-Nephritis-at.html

Slides https://www.fatetherapeutics.com/wp-content/uploads/2025/06/EULAR-FT819-102-oral-presentation-2025.pdf

Still early days with few treated, but with responses, good safety profile, no Flu (or no LD chemo) and being off-the-shelf are all positives.

[NY1972]

I think CARNK, NK just keep a whole bunch of PhDs employed, not much else. Lack of durability and expansion make them useless in AID, solid cancers

[jondoeuk]

A new paper https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00220-X

[jondoeuk]

One way to make CARs more (antigen) sensitive https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00060-1

This is based on the discovery that low levels of antigen resulted in diminished Linker of T-cell Activation (LAT) utilisation downstream of the CAR. The incorporation of a second, LAT-containing CAR leads to significantly higher levels of LAT activation upon antigen stimulation.

[NY1972]

Moving 819 to Main St.
ChatGPT couldn’t find any indication that Providence Medical Foundation in Fullerton operates a CAR?T-cell therapy center. CAR?T treatments are highly specialized and typically limited to major academic medical centers or flagship cancer institutes.

[NY1972]

NKTX needs FLU to deplete long lived B cells or CARNK that target BCMA. CGEM mgt said CD19 TCE has PK issue in BM.

[jondoeuk]

You would want NKTX's therapy to show results as good as this, if not better https://investorshub.advfn.com/boards/read_msg.aspx?message_id=176260701

As for TCEs, from this: ''Over time, 12 of 14 patients treated with blinatumomab relapsed, after a median durability of response of 5.5 [2–18] months.'' https://scientific.sparx-ip.net/archiveeular/index.cfm?view=1&c=a&searchfor=TCEs%20&item=2025ABS0364

[NY1972]

NKTX, CGEM .. AID is no easy picking
Short CD19 TCEs remissions is my guess.
Cullinan Therapeutics. “Adding a BCMAxCD3 bispecific T cell engager to our pipeline complements our rapid global clinical development of CLN-978"

[jondoeuk]

Thread

🧵1/
T cells have deservedly been in the🔦for #cancer #immunotherapy, but other engineered cell therapies are now📈. What mediates NK cell exhaustion remains an important unanswered❓.

📄Link: https://t.co/dQIK4fVkxO

I’m so thrilled🥳to share our work out now🚨@Nature… pic.twitter.com/4EKNxr7Hne

— Hind Rafei (@HindRafei) June 4, 2025

[jondoeuk]

''Nova Biotechnology (Suzhou) Co., Ltd. (Nova Biosciences), a R&D company focused on TCR-T immune cell therapies for solid tumors, announced that it has signed a non-exclusive license agreement with BeiGene to license the rights to an antigen-specific TCR molecule developed by BeiGene for the development of next-generation generic cell therapies based on the iPSC platform.'' https://mp.weixin.qq.com/s/x8xur0IDjEY5KGizwoOZAA

[jondoeuk]

A number of Chinese companies are developing auto CAR-T's secreting TCR-mimic mAbs.

Another company developed a bispecific fusion protein platform. Data from two ongoing trials https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT144/761649/Abstract-CT144-Phase-I-investigator-initiated https://aacrjournals.org/cancerres/article/85/8_Supplement_2/CT145/761648/Abstract-CT145-Phase-I-investigator-initiated

[jondoeuk]

From this: ''Maus said that the hospital has spun out a company around the glioblastoma CAR-T therapy, although it is still in stealth mode.'' https://endpoints.news/asco25-brain-cancer-cell-therapies-make-early-strides/

So auto CAR-T's secreting BiTEs.

[NY1972]

MUC16/WT1
https://pmc.ncbi.nlm.nih.gov/articles/PMC10197740/?utm_source=chatgpt.com

[NY1972]

Hope FATE learn from ADAP. in picking cancer type to tackle. May be they should try melanoma with TCE targeting Prame?
synovial sarcoma Sarcomas Other Solid Tumors
MAGE-A4 expression High and uniform Variable or low
Antigen presentation Usually intact Often impaired
TME Less suppressive Highly immunosuppressive
HLA loss Rare Common in some
Fibrosis Less dense More dense

[jondoeuk]

BiTEs can be more (antigen) sensitive than CARs, some approaching TCR-level sensitivity, but it depends on the design. ADAP's ADP-600 (an auto PRAME-targeted TCR-T cell therapy) is 10x more sensitive than competitor TCRs, including IMTX*.

So if FATE decided to pursue that target (PRAME), they would need to design a BiTE that is as least as good as ADAP's. One problem would be HLA-restriction, but targeting the most frequent HLAs would overcome this**.

* https://www.fiercebiotech.com/biotech/asco-immatics-prame-cell-therapy-tied-56-response-rate-advanced-melanoma-ph-1b-study

** Around 90% of people in the U.S. are positive for at least one of the top six HLAs.

[NY1972]

Sounds like a game changer. BiTEs have been shown to convert regulatory T cells (T-reg) into cytolytic effector cells [37]; thus, this approach could potentially reduce the suppressive tumor microenvironment or convert the suppressive TME to a more immunogenic environment. Picking TCE targeting prame HLA-A*02:01?

https://pmc.ncbi.nlm.nih.gov/articles/PMC10991175/

[jondoeuk]

Without testing it in humans, we don't know.

The only human data (N=3) I'm aware of is this*. Autologous T-cells were engineered with a CAR to recognise EGFRvIII and secrete a bispecific T-cell engager that recognises the normal form of EGFR. There were no SAEs or DLTs. Radiographic tumour regression was rapid, but the responses were transient in two of the three.

* https://www.nejm.org/doi/full/10.1056/NEJMoa2314390

[NY1972]

Local TCE expression. No AE?

[NY1972]

CARNK + LD : 66.7 % (8/12) achieved DORIS remission and 75 % (9/12) achieved LLDAS.

https://scientific.sparx-ip.net/archiveeular/index.cfm?c=a&searchfor=doris%20remission&view=1&item=2025LB0009

[jondoeuk]

(OT)

1/

My 2 cent commentary on running TCE trials in autoimmune.

This trial design is also used in Roche's CD19xCD3.

It demonstrate how hard it is to run trials. https://t.co/8BDhX2ph1n

— Jing Liang 🇺🇦 (@AppleHelix) May 30, 2025

[jondoeuk]

(OT) CAR-NK scFv affinity https://jitc.bmj.com/content/13/5/e012139

[jondoeuk]

A new paper: ''Here we illustrate surface expression of a CD3 fusion receptor (CD3FR) in iPSC-derived CAR T (CAR iT) cells, enabling TCE-mediated targeting of diverse antigens. In vitro and in vivo, CD3FR+ CAR iT cells demonstrated potent cytotoxic response and cooperative activity against mixed tumor lines and multiple antigens. CD3FR+ iT cells were further engineered to secrete TCEs, eliminating the need for extra supplementation with TCEs.'' https://pubmed.ncbi.nlm.nih.gov/40443031/

[NY1972]

Dual BCMA, CD19 CAR design to achieve BM PK req'd. Flu not needed
New data demonstrate 92% of patients now meet DORIS complete remission criteria


https://www.businesswire.com/news/home/20240612055623/en/iCell-Presents-Positive-New-Follow-up-Clinical-Data-Confirming-BCMA-CD19-cCAR-Safely-Delivers-Long-term-Medication-Free-Complete-Remission-from-Systemic-Lupus-Erythematosus-Lupus-Nephritis-at-EULAR-2024

[jondoeuk]

The posters

1 https://www.fatetherapeutics.com/wp-content/uploads/2025/05/Sword-and-Shield_ASGCT-2025-vFinal.pdf

2 https://www.fatetherapeutics.com/wp-content/uploads/2025/05/2025-ASGCT-UPAR-poster-FINAL.pdf

3 https://www.fatetherapeutics.com/wp-content/uploads/2025/05/ASGCT_2025-FT836_Vfinal.pdf

4 https://www.fatetherapeutics.com/wp-content/uploads/2025/05/ASGCT_FT839_Vfinal.pdf

5 https://www.fatetherapeutics.com/wp-content/uploads/2025/05/FT522-101-ASGCT-2025_vFINAL.pdf

[NY1972]

CY is approved by FDA for SLE. They are same class of drug. FLU is req'd because it depletes B cells in BM, not CARNK or CART. 819 express high CXCR4.

[jondoeuk]

It could slow down recruitment.

Also, I don't know why they didn't look at testing single-agent bendamustine https://jitc.bmj.com/content/12/7/e008975

[jondoeuk]

No, but the fact that rapid and effective depletion of circulating B-cells was observed after the first cycle is encouraging as for some autoimmune diseases, complete or near-complete depletion may be needed in order for a reset. However, trafficking, infiltration, and function in secondary and tertiary tissues are going to play a role in the latter.

[jondoeuk]

Either they are not confident using Cy only, or early data is showing it is not working that well (or worse). Or maybe they are confident (using Cy only) but want to test both in order to put the data out there. As (at least a few) patients have been dosed, I think the former could be more likely.

[NY1972]

NKTX can't skip FLU
In order to maximize success in our trials, we have incorporated a lymphodepletion regimen utilizing both cyclophosphamide and fludarabine. Similar trials have established this combination, and we believe there is value in producing a comparable dataset while still continuing our cyclophosphamide-only regimen for eligible patients.

[NY1972]

Looking at the pipe and listening to the CEO, CAR T is the future. It is much higher bar compare to NK. ADAP failed to deliver ipsc TCR T after spending 100M from Roche.

[NY1972]

The duration of B cell aplasia had no impact on DORIS remission. If the CART dosage is high enough to deplete all the EBV+ B cells, the % of CART able to evade and survive long term doesn't matter since there is no malignant clones to outlive them.

[jondoeuk]

I don't think evasion is necessary in SLE since all the SLE pts in AUTL trial achieved DORIS remission.

AUTL's therapies are all autologous.

So it comes down to persistence and BM infiltration for CARNK.

IPSC ran a PhI trial of CNTY-101 in R/R CD19+ B-cell malignancies. The trial enrolled patients who had relapsed following at least two prior lines of therapy, including prior autologous anti-CD19 CAR-T cell therapies. Two dosing schedules were evaluated, either a single CNTY-101 infusion per cycle in Schedule A, or three weekly infusions of CNTY-101 per cycle in Schedule B. Patients received lymphodepletion prior to the first cycle of CNTY-101, and prior to the second cycle, if lymphodepletion was tolerated, patients could then receive additional cycles of treatment without subsequent lymphodepletion.

Twenty-three patients were treated and for the highest dose levels DL3B (1 billion cells in each of three weekly doses per cycle) and DL4B (3 billion cells in each of three weekly doses), the ORR was 77% (CR rate was 22%). Deep B-cell depletion was observed through the initial treatment cycle, while repeat-dosing cycles led to persistent exposure in the presence of an intact endogenous immune system.

CNTY-101 was shown in some patients to persist outside of the circulation and was detectable in tissues by cfDNA (+/- biopsies).

FATE made a smart decision when it gave up on NK after J&J cut tie.

FATE is developing next-gen iNKs for oncology, autoimmunity and senescence.

AUTL is wasting their cash on 3 year trial.

They are expanding the AUCATZYL (approved in the US, the UK and soon the EU for R/R ALL) opportunity into other B-cell malignancies, as well as autoimmunity. Severe refractory lupus nephritis is a high unmet medical need. If successful, will expand into earlier lines.

FLU is a nonstarter for AID plus 10 day hospital stay is too expensive.

Until something better comes along.

[NY1972]

I expect CARNK efficacy to be the same as MRNA CART. Both don't proliferate

33% (4/12) of participants achieved minimum symptom expression (MSE), defined as an MG-ADL score of 0 or 1, at Month 6, all of whom maintained MSE through Month 12.

83% (10/12) of evaluable participants maintained a clinically meaningful response through Month 12. Clinically meaningful response is defined as a reduction in MG-ADL score of at least 2 points.

https://finance.yahoo.com/news/cartesian-therapeutics-descartes-08-observed-110000924.html

[Monksdream]

FATE, under $2

[NY1972]

I don't think evasion is necessary in SLE since all the SLE pts in AUTL trial achieved DORIS remission. So it comes down to persistence and BM infiltration for CARNK. FATE made a smart decision when it gave up on NK after J&J cut tie. AUTL is wasting their cash on 3 year trial. FLU is a nonstarter for AID plus 10 day hospital stay is too expensive.

[jondoeuk]

ipsc is Clade + allo evasion

IPSC had been developing its own iPSC-derived therapies and allo evasion before the acquisition of Clade. The latter gave them the iPSC-derived ab CD4+/CD8+ T-cell platform and better allo evasion.

Looks like they are 2-3 years behind 819.

A multicenter trial is now evaluating CNTY-101 (an anti-CD19 CAR-iNK) in SLE, LN, IIM and DcSSc. An investigator-initiated trial by Drs. Georg Schett and Andreas Mackensen will start soon as well. So around ASH they could present early data.

I know AUTL has an ongoing trial and they presented preliminary data from an initial six patient cohort with SLE. It supports progressing obe-cel (an auto anti-CD19 CAR-T) into a planned single-arm pivotal phase two (N=30) trial in severe refractory, active lupus nephritis. The first patient is expected to be dosed by the end of the year. The primary endpoint is complete renal response at 6 months. The secondary endpoint is DORIS at 6 months.

Trying the different approaches is a great idea if these bios are frugal. IPSC will be bankrupted based on the current burn rate.

They have newly prioritised programs and the cash runway is estimated to extend into the fourth quarter of 2026.

[NY1972]

I see. ipsc is Clade + allo evasion. Looks like they are 2-3 years behind 819. Trying the different approaches is a great idea if these bios are frugal. IPSC will be bankrupted based on the current burn rate.
Century’s newly expanded and diversified pipeline incorporates additional next-generation iNK and iT programs spanning targets in cancer, and autoimmune diseases. These programs include CLDE-308, an aß iT cell program targeting CD19 in autoimmune disease and B-cell malignancies, CLDE-361, an aß iT cell program targeting BCMA in myasthenia gravis, and an undisclosed iT cell focused research program in solid tumors.

[jondoeuk]

Given its (LD chemo) role, I think different regimens still need to be tested. In one trial (of an auto anti-PSCA CAR-T therapy in mCRPC), lower-dose cy still yielded greater CAR-T activity than in the absence of LD chemo. It had lower tox as well.

Taxanes, platinum and other agents, as well as (low-dose) radiotherapy have shown potential to modulate the tumour microenvironment https://www.cell.com/molecular-therapy-family/oncology/fulltext/S2372-7705(20)30093-0 https://www.tandfonline.com/doi/10.4161/onci.25962 https://www.sciencedirect.com/science/article/pii/S1525001618304490

However, additional strategies could still be needed as previous trials of CAR-T therapies have shown tumour microenvironments becoming even more immunosuppressive after administration. Here is one paper https://www.science.org/doi/10.1126/scitranslmed.aaa0984

As for Gadeta, they were acquired by Clade Therapeutics in Oct 2023. IPSC acquired Clade in April 2024. I know the approach is feasible as there was an oral presentation (from memory) at AACR 2023 or 2024 (showing activity) in R/R AML patients.