Fate Therapeutics Inc (FATE)

I think in vivo mRNA is waste of time, RNAC ex vivo required 6 doses because mRNA CART don't proliferate or persist

It's too early to say. They have only just started dosing the first healthy volunteers*. We don't know about the biodistribution of the tLNP or if it is able to modify only CD8-expressing T-cells in humans.

Even if it modifies only CD8-expressing T-cells, the T-cells will transiently express the CAR. The next question is do the T-cells in the primary, secondary, and/or tertiary tissues express the CAR long enough (and expand) to enable the required B-cell depletion to induce an 'immune reset.'

As for FT819, we could know in Oct (or Dec) if a registrational trial will happen.

* https://www.businesswire.com/news/home/20250611668181/en/Capstan-Therapeutics-Announces-Initiation-of-Phase-1-Trial-of-Lead-In-Vivo-CAR-T-Therapy-CPTX2309-for-Treating-Autoimmune-Disease

The safety profile (so far) is concerning.

That seems the case with many Chinese biotech companies.

Genocury Biotech website is a shell

Also https://www.curetoday.com/view/in-vivo-cd19-car-t-leads-to-remission-in-dlbcl-without-lymphodepletion

Another (but they used LD chemo) https://jitc.bmj.com/content/12/Suppl_3/A1712

A case series on four patients treated with ESO-T01 (a nanobody-targeted, immune-shielded lentiviral vector for in-vivo T-cell engineering with a humanised anti-BCMA single-domain-antibody CAR) https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01030-X/fulltext

''As of April 1, 2025, all patients completed the 2-month follow-up, with the first two patients completing the 3-month follow-up. Patient 1 attained a stringent complete response with resolution of all medullary and extramedullary lesions by month 2 (appendix p 4), whereas patient 2 had a stringent complete response with complete lesion resolution by day 28 (appendix p 4). Patients 3 and 4 had partial responses, with tumour lesions reduced and minimal residual disease negativity reached in the bone marrow by day 28 (appendix p 4, 9). At the 2-month follow-up, serum protein electrophoresis and free light chain concentrations (appendix p 9) returned to normal in patient 3 and were further reduced in patient 4.

CAR T cells in peripheral blood were first detected on days 4–8 and peaked on days 10–17, and were also detectable in the bone marrow, tumour tissues, pleural effusions, and CSF (figure D; appendix pp 5, 9). In patient 2, immunohistochemistry of baseline and day 10 tumour biopsies revealed marked reduction of CD38+CD138+BCMA+ tumour cells alongside significant CD3+ T-cell infiltration in the tumour microenvironment (appendix p 5).

We then analysed the phenotypic profile of CAR+ T cells at the expansion peak (appendix p 5). Patient 1 had a higher proportion of CAR+ T cells with a central memory phenotype, whereas patients 2 and 4 had a greater abundance of naive and central memory CAR+ T cells. Effector and CD28–CD57+ senescent T cells were enriched in CAR+ T cells of patient 3, which corresponded to unfavourable CAR T-cell expansion. Flow cytometry of CAR T cells in peripheral blood showed a low CAR expression in CD3– lymphocytes and natural killer cells (appendix p 5). Nonetheless, off-target transduction in haematopoietic cells and other immune cells requires further study, and tumourigenicity needs to be monitored through long-term follow-up.''

From ChatGPT:
Without CXCR4, T cells—including CPTX-2309–transfected ones—are unlikely to efficiently home to the bone marrow. If BM trafficking is crucial to the therapy's success, co-expression of CXCR4 or modification to preserve/enhance its signaling would be necessary.

It is an excuse for abbv to pay off friends? LNP is known to congregate to liver. So invivo CART will turn CD8+ cells into CART for a few days. What is going to them migrate to BM from liver?

Not sure how cytokine engineering will help. AUTO and ALLO CART and NK need FLU to deplete B cells in BM even though they don't want to admit it. They can't turn the clock back to make the cells stem like with high CXCR4, TCF1..

Yes, but the Chinese company did present preclinical data on enhancing CAR-T cell functions without lymphodepletion via engineering cytokine pathways. Based on this, I don't think it's unreasonable to think they will look to do something similar for CAR-NKs.

NY, Jon, have lurked for over 2 years and appreciate your commentary. I felt the need to make an account today when I saw the news on this ABBV acquisition of Capstan Therapeutics.

How does this early trial announced days before their acquisition compare FT819 prospects? I have rarely seen M&A so early in pre-clinical/Ph1. FATE seems to have received favorable sentiment after this news. I appreciate your insight as your scientific intuition is far beyond my understanding.

https://news.abbvie.com/2025-06-30-AbbVie-to-Acquire-Capstan-Therapeutics,-Further-Strengthening-Commitment-to-Transforming-Patient-Care-in-Immunology

Do you think their PhDs working on a CART that express both BiTE and anti CD47 Ab?

Just like NKTX CD19 alloNK in terms of preconditioning.

819 has high CXCR4. With 1XX CAR , it is iNK + proliferation + persistence

In addition to tumor burden, we also analyzed the PK of iNKs in BM and PB. The number of iNKs
in the BM of the CXCR4GZMB group was significantly higher than those in the BFPGZMB group by
approximately 20-fold on both day 10 and 21 (P < 0.01, Figure 5E), but with comparable PK in
PB. Through the cell cycle analysis, the superior in vivo efficacy of CXCR4GZMB iNKs is mediated
by increased BM homing capability, not by IL15 and CXCL12 induced cell cycle change

The company is developing other iPSC-derived CAR-NK and CAR-T cell products, as well as HD-derived CAR-T cell products, including https://www.sciencedirect.com/science/article/pii/S2666379124006608 https://www.cell.com/trends/biotechnology/fulltext/S0167-7799(25)00081-2 https://www.businesswire.com/news/home/20250514459901/en/Qihan-Biotech-Presented-its-Breakthrough-CAR-T-Research-at-ASGCT-2025

''The patient is a 36-year-old woman who has been suffering from refractory diffuse cutaneous sclerosis for nearly twenty years. She first developed Raynaud's phenomenon at the age of 16 with a strong positive (+++) anti-Scl-70 autoantibody. At the age of 18, she began to experience thickening of the skin, gradual erythema and joint pain in her hands and limbs. Over time, skin hardening extends to the face, neck, and chest, leading to severe dysfunction. Although the lungs are normal, interstitial lung disease (ILD) was detected by chest CT three years ago. Her condition deteriorated despite years of multiple treatments, including methylprednisolone, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tocilizumab and nidabib ethanesulfonate. Patients were first treated with QN-139b at a dose of 6e8 cells on August 4, 2024, for a total of four doses (D0, 3, 7, 10 days). After 6 months of follow-up, the overall safety profile of QN-139b was good, and patients did not complain of particular discomfort. In the clinical evaluation, the patients complained of significant improvement in the overall disease, which was objectively manifested by a significant decrease in autoantibodies, a return to normal complement, a significant decrease in mRSS score, and a significant improvement in ACR-CRISS score. Further analysis showed that the patient's pathological B cells were cleared, inflammation and fibrosis were inhibited, infiltrating lymphocytes in the affected skin were removed, and skin micro-vessels were remodelled. QN-139b successfully induced patients to achieve immune reset.''

Yes (flu/cy), with an infusion on days 0, 3, 7, and 10. Up to five others are planned to be enrolled in this compassionate use trial.

Did they use LD to precondition?

AID is a good fit for 1xx CART with cytokine profile similar to endogenous T cells. These T cells can survive in chronically immuno suppressed pts. They persistence is self limiting as the pts. Treg recovers when number of activated T cells diminish. Still waiting for 825 + mAb data, it should work in pts with EGFRmut pts.

The data in AIDs is encouraging. Before Modulus Therapeutics was acquired, their lead anti-CD19 CAR-NK cell therapy was going to use Fnl4 plus CRTAM co-stim domains (I don't think they added the CD3z).



They were conducting additional screening combinations to test different antigen-binding domains, extracellular domains, and transmembrane domains to further enhance the efficacy.

As for solid tumours, it will require more (as a minimum), not just optimal CARs for different indications, but also ways to reduce/stop rejection, optimal receptors for ADCC, cell-intrinsic cytokines, inducing a memory-like phenotype, and possibly ways to overcome TGF-B suppression https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00217-0

(OT) An iPSC-derived anti-CD19/BCMA CAR-NK https://www.cell.com/cell/abstract/S0092-8674(25)00625-7

''This study reports the first-in-human application of iPSC-derived CD19/BCMA dual-targeting chimeric antigen receptor-natural killer (CAR-NK) cells (QN-139b) in a patient with severe, diffuse cutaneous systemic sclerosis. The allogeneic product was genetically edited for reduced alloreactivity and improved in vivo performance, with no structural chromosomal abnormalities detected. The treatment led to significant B cell depletion with minimal toxicity, similar to CAR T cell therapy. The patient showed marked clinical improvements during the 6-month follow-up, including reduced autoantibodies and reversed fibrosis, which are resistant to conventional treatments. Single-cell analysis of peripheral blood revealed that the treatment shifted B cells toward more naive phenotypes and eliminated pathogenic B cells. Proteomic studies demonstrated suppression of inflammation and fibrosis, enhanced tissue regeneration, and improved angiogenesis. Pathological evaluation confirmed the elimination of infiltrated lymphocytes from affected skin along with restored skin and microvascular structure. These findings suggest QN-139b is a promising immune-modulatory treatment for severe autoimmune diseases.''

Cutting loss on the NK with 500M left to pursue ipSC T cells was wise. Discovering AID was luck and timing. I wonder they would ever move away from cancers without Schett CART data.

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!

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

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

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.

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

$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

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.

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.

FT596 is not even included in their pipe.

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

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

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

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.

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

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

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.

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.

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

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

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"

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

''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

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

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.

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

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

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.