Fate Therapeutics Inc (FATE)

[jondoeuk]

(OT) Shinobi announced their $51M Series A funding https://www.prnewswire.com/news-releases/shinobi-therapeutics-launches-with-completion-of-51m-series-a-to-advance-hypoimmune-ips-t-cell-therapy-platform-302012188.html

Targeting tech https://www.cell.com/molecular-therapy-family/methods/fulltext/S2329-0501(23)00148-1

Immune evasion tech https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00365-X

[jondoeuk]

From last year https://finance.yahoo.com/news/cellorigin-announced-treatment-first-patient-170000142.html

[jondoeuk]

DNA has acquired Modulus Therapeutics' cell therapy platform assets, including their CAR and switch receptor libraries https://www.prnewswire.com/news-releases/ginkgo-bioworks-acquires-modulus-therapeutics-cell-therapy-assets-to-strengthen-next-gen-car-designs-302105056.html

[jondoeuk]

From this paper https://www.nature.com/articles/s41540-024-00355-3




Adoptive T-cell therapy also benefits from the combined activity of CD4+ and CD8+ T-cells, but FT819 is a CD8+ only T-cell therapy https://www.nature.com/articles/s41417-020-0183-x https://www.sciencedirect.com/science/article/pii/S0952791521001230 https://www.sciencedirect.com/science/article/pii/S0304419X2030158X https://www.science.org/doi/10.1126/science.1251102 https://www.nejm.org/doi/10.1056/NEJMoa0800251 https://www.science.org/doi/full/10.1126/sciadv.abe3348 https://www.science.org/doi/full/10.1126/sciadv.aba7443

[jondoeuk]

1338 / 21 - Novel activation domains coupled to chimeric ILT receptors (CIR) enhance NK cell targeting of HLA-G+leukemic and solid tumor cells https://www.abstractsonline.com/pp8/#!/20272/presentation/6031

[jondoeuk]

AACR abstracts

3618 / 24 - High-avidity BCMA CAR and high-affinity, non-cleavable CD16 Fc receptor incorporated in off-the-shelf CAR T cells promote multi-antigen targeting and durable anti-tumor cytotoxicity in the treatment of multiple myeloma https://www.abstractsonline.com/pp8/#!/20272/presentation/7153

3995 / 4 - A novel chimeric Fas signal redirect receptor enhances the durability of anti-tumor activity and serial killing potential of CAR T cells https://www.abstractsonline.com/pp8/#!/20272/presentation/6132

5240 / 15 - Novel CD3-Fusion Receptor enables combination of T-cell engagers and allogeneic CAR T cells to promote enhanced antitumor activity and overcome antigen escape https://www.abstractsonline.com/pp8/#!/20272/presentation/6056

[jondoeuk]

Not many are in development. I know the PI of the trial in Germany said one of the chemo drugs used for lymphodepletion is (likely) playing a role as well.

[harry crumb]

Fate always makes money again $$$$

[NY1972]

No place to hide for many CARNK, CART bios

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1335998/full?utm_source=S-TWT&utm_medium=SNET&utm_campaign=ECO_FIMMU_XXXXXXXX_auto-dlvrit

[Monksdream]

FATE new 52 week high

[NY1972]

ACTs are turning into migrants armed with a pistol and name looking for a felon. They don't know the hoods and the local sheriffs. How long can they last in the hostile ground?

[jondoeuk]

Far more are going under quietly and unnoticed https://www.fiercebiotech.com/biotech/catamaran-sends-out-life-raft-financing-challenges-claim-another-biotech

[jb128]

Got back in a few months ago. Can we see another run to $120 like back in 2020-21 please??

[harry crumb]

Very nice run to 6 again

[jondoeuk]

(OT) Artec Biotech is built upon methods for differentiating iPSCs into NK cells, as well as proprietary modifications. One example is the alteration of checkpoint receptors, such as PD-1 KO, which will be used for ART-002. The lead is ART-001, an unmodified NK product.

Although iPSC-NKs and PB-NKs of the same donor exhibited similar gene expression profiles, analysis revealed notable differences in genes that are important for NK cell function. Some of these genes were highlighted. Given the success of checkpoint inhibition in treating certain types of cancer, they evaluated checkpoint receptor expression in iPSC-NKs compared to PB-NKs. As demonstrated by a recent study, the expression of multiple checkpoint inhibitors was significantly higher in CD73+ cells, and the frequency of CD73+ cells correlated with larger tumour size in breast cancer patients https://www.jci.org/articles/view/128895

In their differentiation system, they produced NKs with down-regulated CD73 expression.

The next gene of interest was PTGER4, which encodes prostaglandin E2 receptor 4 (EP4). In NK cells, the binding of prostaglandin E2 to the receptor can initiate immunosuppression. In contrast, EP4 inhibition has been shown to enhance NK antitumour activity https://www.tandfonline.com/doi/full/10.1080/2162402X.2021.1896643

EP4 was down-regulated.

TIGIT was another gene of focus. Although not expressed in iPSC-NKs, it was highly expressed in PB-NK control. Overall, TIGIT is variably expressed in human NKs. Notably, NKs with lower TIGIT expression have exhibited higher cytokine secretion capability, degranulation activity, and cytotoxic potential https://onlinelibrary.wiley.com/doi/10.1002/eji.201545480

Furthermore, blocking TIGIT expression via monoclonal antibodies alleviated NK exhaustion https://www.nature.com/articles/s41590-018-0132-0

Similar to TIGIT, cytokine-inducible Src homology 2–containing protein (CIS), encoded by the CISH gene, is also involved in cytokine secretion. CIS is a member of the suppressor-of-cytokine signaling family of proteins. CISH deletion in either iPSC-NKs or PB-NKs increases their sensitivity to IL-15 and enhances JAK/STAT and mTORC1 signaling. This leads to increased NK metabolic fitness that contributes to an improved antitumour response https://ashpublications.org/blood/article/137/5/624/463715/Targeting-a-cytokine-checkpoint-enhances-the

Their iPSC-NKs have significantly down-regulated CISH expression compared to PB-NKs.

Aside from direct mechanisms that tumours employ to down-regulate NK function, the tumour microenvironment also impairs NK function by negatively affecting NK metabolism https://www.frontiersin.org/articles/10.3389/fimmu.2019.02278/full

Enhancing NK metabolic functionality is currently being pursued as one of the avenues for increasing NK cell activity against tumours https://www.pnas.org/doi/10.1073/pnas.2107507118

Considering this, they further evaluated the metabolic profile of iPSC-NKs and PB-NKs. The assessment focused on significantly expressed genes, which impact NK metabolic function. The following genes showed up-regulation in iPSC-NKs: Slc2a1 (involved in glucose transport), Slc7a5 (an amino acid transporter), Slc3a2/CD98 (an amino acid transporter), and TFRC/CD71 (involved in receptor-mediated iron uptake). These data yield insight into the efficacy of iPSC-NKs because nutrient transport is essential and increased expression of nutrient transporters promotes an increased metabolic rate, as well as elevated NK activity https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02377-8

[jondoeuk]

From last year (presented at SITC) https://jitc.bmj.com/content/11/Suppl_2/A1763

[jondoeuk]

(OT) oNKo-innate is a discovery-stage biotech company dedicated to target identification and preclinical IO (drug) development.

In this, the functional genomics and target discovery team have used their platform to perform enrichment screens in primary human NK cells, identifying novel IL-15 axis regulators that contribute to survival and persistence. Phenotypic screens similarly revealed regulators of NK cell cytotoxicity and interferon gamma production. By validating these targets, the team has demonstrated that they are able to regulate various aspects of NK and CAR-NK cell function.

[jondoeuk]

FT825/ONO-8250 update https://finance.yahoo.com/news/fate-therapeutics-announces-initiation-phase-130000499.html

[Lilman72003]

Took my chips off the table and cashed out. $fate has worked in my favor I beat the street. In sub $2 out @ $4.50.

Thank you to the posters here I enjoyed the scientific discourse even if it was way over my head

[jondoeuk]

Looks like the inducement grant was for Dr. Cooley's replacement. Given the company's history, I was hoping that there would be a new CEO.

[Lilman72003]

Took my profits, playing with house money riding freebies.

[jondoeuk]

Using CRISPR screening of metabolic genes, they found that KEAP1 played an important role in the pro-inflammatory activity of macrophages through inhibiting the production of itaconate. As ACOD1 is the sole enzyme to generate itaconate, ACOD1 knockout promoted pro-inflammatory activity of macrophages and enhanced the function of CAR-Ms derived from iPSCs https://www.nature.com/articles/s41467-023-41470-9

[jondoeuk]

Preprint https://www.biorxiv.org/content/10.1101/2023.12.10.570687v1

[jondoeuk]

Phase I Study of FT538 + Daratumumab for Treatment of r/r AML https://ash.confex.com/ash/2023/webprogram/Paper189132.html

FT538, iPSC-Derived NK Cells Are Potent Inducers of Apoptosis in AML Cells and Their Effect Is Synergistic in Combination with Approved Therapeutic Strategies https://ash.confex.com/ash/2023/webprogram/Paper187192.html

iPSC-derived natural killer cells expressing the FcyR fusion CD64/16A can be armed with antibodies for multitumor antigen targeting https://jitc.bmj.com/content/11/12/e007280

[jondoeuk]

More preclinical data https://www.nature.com/articles/s41590-023-01687-8

[jondoeuk]

Enhancing cell therapy & regenerative medicine: advanced iPSC genome engineering via Logomix Genome-Writing platform https://jitc.bmj.com/content/11/Suppl_2/A1803

[jondoeuk]

New pipeline

[jondoeuk]

In that paper they were detectable for only 48 hours. NKs have an effective half-life of 1-2 weeks, memory-like longer, with early data (in H&N with anti-CTLA-4* and N-803) showing persistence out to at least 40 days.

* CTLA-4 blockade seems to impact phenotype with a skewing towards CD16+CD57+.

[jondoeuk]

Yes, that was one of at least five (from memory) trials testing aNKs (non-engineered NK-92s).

In metastatic pancreatic IBRX tested low-dose nab-paclitaxel, gemcitabine, aldoxorubicin, cyclophosphamide, low-dose SBRT, N-803 (an IL-15 superagonist) and PD-L1 CAR-NKs.

In all patients (3rd to 6th line) mOS is 5.8 months; median PFS 2.3 months. In 3rd line, mOS is 6.3 months. While this exceeds historical results, there were no controls.

Going forward (for other types), they plan on adding a number of other agents, including a heterologous prime-boost vaccine.

[NY1972]

It is given weekly. So persistence is not an issue.

[NY1972]

It is given weekly. So persistence is not an issue.

[NY1972]

NIH used it.
To test the effectiveness of irradiated PD-L1 CAR-NK cells, combined with pembrolizumab and N-803, in people with advanced forms of gastric or head and neck cancer.

https://classic.clinicaltrials.gov/ct2/show/NCT04847466?term=CAR+NK&recrs=a&draw=9&rank=20

[jondoeuk]

It is a transformed cell line, so must be irradiated prior to administration. In previous trials, this has (perhaps) been responsible for the limited persistence observed, only a few days https://www.isct-cytotherapy.org/article/S1465-3249(13)00603-8/fulltext

[NY1972]

Combined treatment with anti-PSMA CAR NK-92 cell and anti-PD-L1 monoclonal

[jondoeuk]

Using NK-92 cells?

[NY1972]

They are testing the combo in China.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9191826/

[jondoeuk]

Has any bio co-cultured their CARNK with TAM and cancer cell lines?

No, but one of the co-founders of Shoreline showed that while macrophages alone did not kill AML blasts, the addition of NKs (both without a CAR) significantly improved killing of AML blasts by half. The addition of an anti-CD47 mAb further increased killing by 23%.

Another (academic) group has created iPSC-derived CAR-macrophages, CAR-NKs, CAR-eosinophils, and CAR-neutrophils. Some of the preclinical data shows that both CAR-M and CAR-NK suppressed cancer cell survival more efficiently than either alone, even at higher doses of these cells. Also that the phagocytosis activity of CAR-M was increased in the presence of CAR-NK. In addition, CAR-eosinophils improved CAR-NK activity, and CAR-M with CAR-eosinophils enhance the activity of CAR-NK.

Anyone testing CARNK + ATEZO?

Not that I'm aware. One group showed that combination of allo NKs with pembrolizumab was well-tolerated and improved PFS and OS in patients (with NSCLC) compared with pembrolizumab alone https://www.jci.org/articles/view/132712

Also, a PhI testing allo tumour-reactive PD-L1+ NKs engineered to express soluble IL-15 in patients with NSCLC refractory to PD-1/PD-L1 inhibitors is ongoing.

[NY1972]

Has any bio co-cultured their CARNK with TAM and cancer cell lines? Anyone testing CARNK + ATEZO?

[jondoeuk]

Disruption of TGF-b signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells https://jitc.bmj.com/content/11/Suppl_1/A354

Engineering Superaffinity Antibody Dependent Cellular Cytotoxcity Receptors into iPSC-Derived NK Cells As Next-Generation Immunotherapies for Cancer https://ash.confex.com/ash/2023/webprogram/Paper181261.html

Human iPSC-Derived NK Cells with Knock-in of the BCL2 G101V Mutation Are Resistant to Venetoclax and Demonstrate Improved Anti-AML Activity In Vivo https://ash.confex.com/ash/2023/webprogram/Paper177527.html

[jondoeuk]

Preclinical data (presented at SITC) on FT825 https://jitc.bmj.com/content/11/Suppl_1/A307

Also https://jitc.bmj.com/content/11/Suppl_1/A414

[jondoeuk]

The SITC presentation highlighted the latest updates on NKILT Therapeutics' engineered CIR-NK cells with proof-of-concept in vitro data against leukaemia cells expressing HLA-G https://jitc.bmj.com/content/11/Suppl_1/A290

The ASH, an oral presentation will feature details of the proprietary activation domains that enhance activity of the CIR-NK engineered cells against HLA-G-positive acute myeloid leukaemia cells. The presentation will expand preclinical data with a specific focus on these novel activation domains and will characterise the serial killing activity against AML cells https://ash.confex.com/ash/2023/webprogram/Paper190073.html

[harry crumb]

Patience, loading shares now is money! $$$$$

[Lilman72003]

Setting up like a dream.

Need volume to send her into orbit

[Lilman72003]

bouncing off the double bottom

[Lilman72003]

flippers selling for beer money

[NY1972]

With all the PD1 combos failures, pharmas are going back to poisoning cancers with hundreds ADC. No survival benefits but lots AEs for the longer PFS.

[NY1972]

Immune cells are acting like bios traders, stocking up on PD-L1 when the body is inflammed. Tumors are exploiting this habit and makes tons of PD-L1 for their consumption. Repeated admin of Chemos just create more DNA damaged cells to further promote this process.

[Lilman72003]

they call me D’Angelo Russell cuz I’m #loading

[jondoeuk]

Trogocytosis has been documented for other leukocytes, including T-cells. In this paper, CAR-T cells were also shown to exhibit it when co-cultured with different types of cancer cells, including CARs that used the high-affinity CD19 binding domain FMC63 (most CAR-T therapies use it) https://www.nature.com/articles/s41586-019-1054-1

Similarly, it can be triggered by engagement of the CD16 receptor on NKs with mAbs leading to reduced efficacy https://ashpublications.org/blood/article/125/5/762/34055/Fc-receptor-mediated-trogocytosis-impacts-mAb https://aacrjournals.org/clincancerres/article/22/21/5211/79645/Checkpoint-Inhibition-of-KIR2D-with-the-Monoclonal

In this, they investigated if it contributed to (anti-CD19) CAR-NK cell fratricide and tumour progression in patients with lymphoid malignancies treated in a previously reported trial https://www.nature.com/articles/s41591-022-02003-x

Using blood samples collected at multiple time points after CAR-NK cell infusion, patients were divided into two groups based on the overall trogocytosis expression on CAR-NK cells [high (n=4) vs. low (n=7)]. It was found that acquisition of trogocytosised CD19 expression on CAR-NK cells was associated with a reduction in CD19 expression on B-cells and a higher probability of relapse (3 of 4 patients) compared to patients in the low group (0 of 7 patients). Also, expression was associated with improved clinical response. Those with a lower level had improved responses (100% ORR vs. 25% ORR).

They hypothesised that an inhibitory CAR, which incorporated an scFv directed to an NK-specific antigen linked to a inhibitory signal might overcome it. To determine that, they synthesised a CAR that recognised an NK self antigen. This was done by fusing the transmembrane and intracellular domains of a CAR with an scFv targeting CS1, a co-receptor that is expressed on all normal NKs, but absent on most CD19+ lymphoid-derived malignancies.

While this did not impact the extent of trogocytosis, they observed less trogocytosis-mediated in vivo fratricide (NK self killing), as evidenced by the better cell viability, higher persistence and improved effector functions compared with control groups.

So, companies should be able to address it, but I'm not aware of any that currently are.

[NY1972]

Gene editing T cells turning CART into ADC. Without tackling innate immunity that is pro tumor, all TCR, CART, CARNK are bound to fail.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886129/