Fate Therapeutics Inc (FATE)

[NY1972]

How CAR NK bios address this issue? NK can grab PD-L1 too.

Trogocytosis-based generation of suppressive NK cells

https://www.embopress.org/doi/full/10.1038/sj.emboj.7601570#:~:text=Trogocytosis%20is%20a%20fast%20uptake,targets%20material%20exchange%20is%20unclear.

[jondoeuk]

FATE's combined CD54 and CD58 genetic ablation https://www.biorxiv.org/content/10.1101/2023.10.09.557143v1

[jondoeuk]

On the signaling https://www.researchsquare.com/article/rs-1279112/v1

[jondoeuk]

Knockout of siglec-5 and siglec-10 on macrophages https://www.pnas.org/doi/10.1073/pnas.2300366120

[jondoeuk]

They have just moved beyond cancer to autoimmune diseases. Numerous companies are already betting on autoimmune diseases, mostly due to this academic paper https://www.nature.com/articles/s41591-022-02017-5

Competition already includes Novartis, Bristol Myers Squibb, and Johnson & Johnson. The most interesting thing Modulus is doing is to express engineered receptors to try and overcome the lymphodepletion requirement.

[NY1972]

Innate immunity is a team sport. All these CAR NK bios want to do 1 on 1. How the gene edited NK cells behave in the heterogenous TMEs will make the trials more a learning experience.

[jondoeuk]

https://www.businesswire.com/news/home/20230811968506/en/HebeCell-and-Logomix-Announce-Collaboration-for-the-Development-of-Next-Gen-Genomically-Engineered-PSC-NK-Cells/

https://logomix.bio/en-engineering

[jondoeuk]

They are also working on other enhancements, including a responsive cytokine and ways to overcome TIGIT evasion.

[jondoeuk]

Preprint https://www.biorxiv.org/content/10.1101/2023.08.02.551530v1.full

[jondoeuk]

An update on the litigation proceedings against Shoreline Biosciences https://www.briefing.com/in-depth-analysis/content/article?ArticleId=IN20230905060647FATE

[jondoeuk]

Old?

[NY1972]

I gave up on all gene modified ACTs once I found out the price to pay is the capacity to interact with M2, B, T and ... in the TME. CART and CAR/NK look like a cell based ADC to me.

[jondoeuk]

Yes, a barrier to overcome to increase the depth and duration of response. One group showed that depletion of fibroblast activation protein positive cancer-associated fibroblasts helped to reduce myeloid cell accumulation and increase endogenous CD8+ T and NK cell infiltration. CLLS has developed this https://www.cellectis.com/uploads/files/SITC_2022_1.pdf

Also another that targets MUC-1 with tumour-specific IL-12 secretion https://www.cellectis.com/uploads/files/Poster_Cellectis_PE_AACR_2023.pdf

Both could be combined and should synergise together.

[NY1972]

Allo CAR T/NK not going to be durable without engaging endogenous innate cells

https://www.cell.com/cell/fulltext/S0092-8674(23)00642-6?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867423006426%3Fshowall%3Dtrue

[NY1972]

Efficacy and cost. With CBNK, there is less worry on IFN gamma expression and CD16A compared to AUTO PBNK. $2K per 2B allo cells from Artiva. Cheap

[jondoeuk]

Why has AFMD had to go back to zero for LuminICE-203?

[NY1972]

A lot of old CARs will be abandoned on the road. CARs sold by Wall St.

[jondoeuk]

https://www.businesswire.com/news/home/20230710284742/en/Novel-gene-delivery-technology-published-and-licensed-exclusively-to-Cellinfinity-Bio

[jondoeuk]

(OT): https://www.pharmiweb.com/press-release/2023-07-10/phase-1-study-indicates-allogeneic-cytokine-induced-memory-like-natural-killer-cells-plus-n-803-may

The only slide I could find

[jondoeuk]

(OT): In this, the authors developed a novel membrane-bound protein technology to express IL-2 (on the surface of NK-92 cells) inducing autocrine signal for proliferation without IL-2 supplementation https://www.thno.org/v13p1506.htm

[jondoeuk]

From another group https://www.cell.com/iscience/fulltext/S2589-0042(23)01155-0

I know the founder of ONK Therapeutic has talked about (low-dose) bortezomib, which upregulates expression of DR5 sensitising cancer cells to TRAIL-mediated apoptosis https://aacrjournals.org/cancerres/article/66/14/7317/525881/Bortezomib-and-Depsipeptide-Sensitize-Tumors-to

It also upregulates Fas https://journals.aai.org/jimmunol/article/180/1/163/78395/Sensitization-of-Tumor-Cells-to-NK-Cell-Mediated

In addition, Treg depletion is another way that could increase efficacy https://ashpublications.org/blood/article/113/24/6120/25786/Bortezomib-treatment-and-regulatory-T-cell

[jondoeuk]

(OT): CellOrigin Bio is focusing on iPSC-derived innate immune cells for oncology.



Preclinical data https://jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00983-2 https://ashpublications.org/blood/article/140/Supplement%201/9238/487745/The-Second-Generation-of-Human-iPSC-Derived-CAR

Also https://www.biospace.com/article/releases/cellorigin-biotech-announces-global-strategic-collaboration-with-qilu-pharma-to-develop-and-quot-off-the-shelf-and-quot-car-imac-cell-therapy/

[jondoeuk]

(OT): ''The high-affinity and non-cleavable CD16 (hnCD16) is developed and demonstrated a multi-tumor killing potential. However, the hnCD16 receptor activates a single CD16 signal and provides limited tumor suppression. How to exploit the properties of hnCD16 and incorporate NK cell-specific activation domains is a promising development direction to further improve the anti-tumor activity of NK cells.'' https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01455-z

[jondoeuk]

https://www.globenewswire.com/news-release/2023/06/20/2690890/0/en/Replay-and-MD-Anderson-announce-FDA-clearance-of-IND-application-for-first-in-class-T-Cell-Receptor-Natural-Killer-TCR-NK-cell-therapy-for-sarcoma.html

[jondoeuk]

When a DR5 specific TRAIL variant is expressed on NK cells, it significantly enhances their cytotoxicity based on preclinical data.

We now have clinical data from two mAbs https://www.globenewswire.com/news-release/2023/06/02/2681484/0/en/IGM-Biosciences-Announces-Update-on-IGM-8444-Phase-1-Trial-and-Future-Clinical-Development.html

We always need new & better to potentially best-in-class drugs with novel mechanisms of action. Presenting a new- DR5 drug for patients with #chondrosarcoma @ASCO#ASCO23 @CCR_AACR @AACR
-->Started working with 1st gen DR5 targeting Rx in 2012
--> FINALLY we have a 3rd… pic.twitter.com/ksTOFdMkVr

— Vivek Subbiah, MD (@VivekSubbiah) June 11, 2023

[NY1972]

I like the LD before CBNK+ ICE+IL-2 combo. Targeted immunotherapy

[jondoeuk]

(OT): HebeCell raised a $53M Series A https://www.businesswire.com/news/home/20210831005965/en/HebeCell-Raises-53-Million-in-Series-A-Financing-to-Advance-Unique-Off-The-Shelf-PSC-CAR-NK-Products-Into-Clinics



Around 80% of the iPSC-derived CD56+ NK cells also express CD8a as compared with ~30 of PB CD56+ NK cells https://academic.oup.com/stcltm/article/10/s2/S10/6522039

CD56+CD3-CD8a+ NK cells are more cytotoxic than CD56+CD3-CD8a-, indicating iPSC-derived NK cells posses stronger cell killing activity than regular peripheral blood NK cells. There is also both in vitro and in vivo (human) data from other groups https://onlinelibrary.wiley.com/doi/10.1002/cyto.990110316 https://pubmed.ncbi.nlm.nih.gov/1281676/ https://www.nature.com/articles/1700756 https://onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2141.2002.03495.x

[jondoeuk]

If they could upend auto BCMA and/or CD19 CARs, I think it might.

As for HER2, that is partnered with Ono Pharma, a CAR-T, with several edits (CAR uses a CD28zeta mutant that contains one instead of all three iTAMs, TCR knockout, high-affinity and non-cleavable CD16 receptor, IL-7 receptor, CD38 knockout, TGF-R 'switch' receptor, and CXCR2 chemokine receptor).

[NY1972]

FATE's targets BCMA, CD19,.HER2.. make it not investable. Too many ACTs, ADCs targeting the same.

[jondoeuk]

The IND has been allowed by the FDA, and the company is currently conducting trial start-up activities at multiple clinical sites. The PhI is designed to assess a three-dose schedule of FT522 in each of two regimens:

Regimen A - Up to two treatment cycles, with each treatment cycle consisting of conditioning chemotherapy, a single dose of rituximab, and three doses of FT522.

Regimen B - Up to two treatment cycles, with each treatment cycle consisting of a single dose of rituximab and three doses of FT522 (without LD chemo).

Patient enrollment into Regimen A will commence utilising a three-dose schedule of FT522 at 300 million cells per dose. Subject to clearance of dose-limiting toxicities at this initial dose level of Regimen A, patient enrollment into Regimen B will then commence utilising a three-dose schedule of FT522 at 300 million cells per dose. Dose escalation of each regimen may proceed independently.

[jondoeuk]

FT536 preclinical data https://www.cell.com/med/fulltext/S2666-6340(23)00136-8

[jondoeuk]

Fate Therapeutics Leaders Misrepresented J&J Tie, Investor Says https://news.bloomberglaw.com/securities-law/fate-therapeutics-leaders-misrepresented-j-j-tie-investor-says

[jondoeuk]

Those are a novel subset of human NK cells that undergo epigenetic changes in only some individuals. They lack expression of an adapter protein, which results in a multi-fold increase in ADCC activity after CD16 crosslinking.

[jondoeuk]

Encouraging start. I hope they present additional data at ASH. I know NKTX could (or at an investor event) on their anti-CD19 CAR-NK (+/- anti-CD20 mAb) in patients who have failed prior CAR-T therapy.

Also, FATE's trial testing FT522 (+ anti-CD20 mAb) either with or without LD chemo should be underway later this year. It builds on FT596 with CD38 knockout and an alloimmune defence receptor https://www.globenewswire.com/news-release/2021/12/13/2351194/0/en/Fate-Therapeutics-Showcases-Positive-Interim-Phase-1-Data-from-FT596-Off-the-shelf-iPSC-derived-CAR-NK-Cell-Program-for-Relapsed-Refractory-B-cell-Lymphoma-at-2021-ASH-Annual-Meeti.html

[jondoeuk]

(OT): InnDura Therapeutics is a preclinical stage company, with a platform based on licensed technologies developed by Dr. Rizwan Romee at the Dana-Farber Cancer Institute and Professor Jianzhu Chen at MIT that focuses on EVE16 engineering of NK cells. EVE16 is a non-CAR approach that provides enhanced cell killing with greatly reduced exhaustion and fratricide. The EVE16 technology can also be applied to T-cells and other forms of cell therapy https://www.inndura.com/

[jondoeuk]

(OT): The latest license is to Replay Bio and includes the entirety of the US NCI shared neoantigen library for allogeneic TCR-NKs https://www.federalregister.gov/documents/2022/12/30/2022-28404/prospective-grant-of-an-exclusive-patent-license-development-and-commercialization-of-natural-killer

Dr. Rezvani from MDA previously partnered with Takeda for CAR-NK. Now Replay Bio and MDA have created Syena for TCR-NK. Their first target for NY-ESO-1 should be in the clinic soon. Replay was on this podcast where they lay out their strategy https://www.labiotech.eu/trends-news/beyond-biotech-podcast-35-rare-disease-day/

Interesting that the CMO of AZN joined their board this week. Dr. June is on their SAB of course.

[jondoeuk]

Could be high TIL. I know MRK's Keytruda was approved last year by the FDA for patients with MSI-H/dMMR advanced endometrial carcinoma. The ORR was 46%.

[jondoeuk]

If NKX101 is successful, it would establish proof-of-concept, and could enable them to evaluate a broader solid tumour clinical development program.

[NY1972]

GMO is no match to organic NK.
Not counting CART relapsed saved by CD13 +CBNK, AB 101 +CD20 also saved
3 of 4 pts who failed prior CAR-T therapy.

[NY1972]

Why NKTX is not targeting cervical cancer?

NKTX could start by testing NKX101 in HCC, intrahepatic cholangiocarcinoma, and/or surgically resected CRC where only liver metastases remain via locoregional delivery.

[NY1972]

Why endometrial cancer? High TIL + high NK?
Two PRs (pending confirmation) were observed in patients with endometrial cancer, one whose cancer had progressed on prior checkpoint inhibitor therapy

[jondoeuk]

Encouraging data that caused the stock to rise ~8% https://www.globenewswire.com/news-release/2023/05/25/2676763/0/en/Cullinan-Oncology-to-Present-First-Monotherapy-Clinical-Data-for-CLN-619-a-Novel-Anti-MICA-B-Antibody-at-ASCO-2023.html

As for solids, NKTX could start by testing NKX101 in HCC, intrahepatic cholangiocarcinoma, and/or surgically resected CRC where only liver metastases remain via locoregional delivery.

Also, have a collaboration with CRSP to co-develop and co-commercialise two CAR-NK cell product candidates and another that will combine CAR-NK with CAR-T. The first candidate will a gene-edited NK cell targeting CD70 https://jitc.bmj.com/content/9/Suppl_2/A123 https://aacrjournals.org/cancerres/article/82/12_Supplement/5512/700598/Abstract-5512-CBLB-CISH-and-CD70-multiplexed-gene

[NY1972]

All these GMO cells is no match to CBNK. Artiva AB 101 shines with IL2 + CD20

[jondoeuk]

''G-NK cells are associated with improved OS and PFS in trastuzumab-treated patients from both clinical trials and real-world datasets, suggesting their presence may serve as a predictive marker for treatment efficacy.'' https://meetings.asco.org/abstracts-presentations/224823

[harry crumb]

Will load 4.70’ s again

[jondoeuk]

(OT) Indapta Therapeutics announces FDA clearance of an IND for IDP-023, an off-the-shelf NK cell therapy. The trial will explore three different dose levels of G-NK cells alone and in combination with IL-2, with rituximab or daratumumab in patients with relapsed/refractory lymphoma or multiple myeloma. G-NK cells are a specific subset of NKs https://ashpublications.org/bloodadvances/article/5/15/3021/476502/Fc-RI-negative-NK-cells-persist-in-vivo-and

[harry crumb]

Will load the 4.70 area again

[jondoeuk]

It will be interesting to see the design of the CAR-Macs. In this, they designed ways to enhance phagocytosis https://elifesciences.org/articles/36688

In another, the group added CD147 as a transmembrane and intracellular signaling domain to activate the expression of matrix metalloproteinases, which are stimulated by CD147 and can degrade the tumour extracellular matrix to overcome physical barriers https://www.nature.com/articles/s41416-019-0578-3

So, hopefully will look at both. Shoreline also talk about adding an anti-CD47 mAb, but I hope they drop that and look at gene editing https://jitc.bmj.com/content/jitc/9/Suppl_2/A152.full

Building on that would be the local secretion of different molecules https://jitc.bmj.com/content/10/Suppl_2/A396

[jondoeuk]

Speaking of GD2 https://www.nature.com/articles/s41591-023-02363-y

Also, for NKT's; Co-Expression of the IL15-IL15a Complex with a 41BB-Based Chimeric Antigen Receptor Promotes Superior Antitumor Activity in NKT Cells https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=14399

IL-12 Reprograms CAR-Expressing NKT Cells to Long-Lived Th1-Polarized Antitumor Effector Cells https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=14440

Knocking-Down Expression of BTG1, a Key Driver of NKT Cell Exhaustion, Promotes Durable Tumor Control by CAR-NKTs in a Xenogeneic Neuroblastoma Model https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=14441

Harnessing CRISPR/Cas9 Mutagenesis Screening for Rational Design of Next-Generation CAR-NKT Therapy Against Neuroblastoma https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=14777

Tumor-Localized Administration of a-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity Against Solid Tumors https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=14780

High-Throughput Pooled Screen of CAR Library Identifies Essential Signaling Features of CAR-T Cells That Resist Immunosuppression https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=15069

[NY1972]

CGEM MICA/B good enough for a poster. So much for the pan cancer claim. Not good news for NKTX.
A phase 1 dose-escalation study to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamic activity of cln-619 (Anti-MICA/B antibody) alone and in combination with pembrolizumab in patients with advanced solid tumors.