Fate Therapeutics Inc (FATE)

[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.

[jondoeuk]

No, but with NKs you can have a multi-antigen targeting strategy to tackle solid tumour heterogeneity. In this, FATE a MICA/B-targeted CAR-NK was combined with mAbs/engagers, which showed improved activity https://jitc.bmj.com/content/10/Suppl_2/A217

That could have been built on with additional CAR(s), membrane-bound TRAIL variant, FasL, and/or synthetic receptors, such as this https://ashpublications.org/blood/article/140/Supplement%201/7429/491146/A-CD3-Fusion-Receptor-CD3-FR-Uniquely-Enables

[jondoeuk]

A number won't, but both FATE (I'm negative long-term) and NKTX have funding until 2025. Focusing on the former, they have burned through at least $500-650M with nothing to show for it, the market (rightly so) has lost faith in management, and the company is no closer to commercialisation today than they were many years ago. My view is still that FT819/576 don't stand a chance.

[NY1972]

Looking at 250 mil burn, FATE and other bios like NKTX in the west will not survive.

[NY1972]

AFM28 - ADCP.

[NY1972]

Some CEOs won't even PR. AFMD was a tool company so learning to cure will be tough sledding. I will take the working ICEs over some nice CEO any day. If you look at ASCO release today, there will be some nice nuggets coming from SAR443579. a trifunctional Natural Killer Cell Engager (NKCE) targeting the CD123 tumor antigen on cancer cells. I guess 30% ORR got the NKCE the oral session. It looks like AFM24 - ADCP.

[jondoeuk]

A letter (dated April 4th) was received saying the company needed to regain compliance with the minimum bid price listing rule, but management waited until Friday (from memory, after the close) to disclose it. So, trust in management is lacking. Shame they couldn't find a focused CEO as some can turn things around in a relatively short time.

[jondoeuk]

It has advantages as multiple edits can result in chromosomal abnormalities, but there are a number of negative regulators, so deletion could improve antitumour activity https://www.nature.com/articles/ni.3470

Another is knockdown, which DTIL was working on (haven't heard anything since this was published) https://precisionbiosciences.com/wp-content/uploads/2022/07/Pires-M-Allogeneic-CAR-T-Cells-with-Deoxycytidine-Kinase-Knockdown.-SITC.-2021..pdf

[NY1972]

If you listen to DTIL CSO who just left, single edit is 19A/B key advantage

[NY1972]

TME is poorly understood. Mgt. is crossing a fast moving river with eyes closed. They will adjust the strategy. ICE are active in AITL and gastric cancer based on latest data, which made sense since cancer bought up by EBV or H Pyloric are more antigenic by nature.

[jondoeuk]

Clearly active (I wonder if they plan to test with NKs?), but the company seems poorly managed.

[jondoeuk]

An IIT (in China) testing this (using the same CLDN18.2-targeted CAR) has now started https://aacrjournals.org/clincancerres/article/26/20/5494/82735/Coexpression-of-IL7-and-CCL21-Increases-Efficacy

Also, new preclinical data on an FAP-targeted CAR https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04080-z

Plus a preprint (again, looking at FAP-targeting) https://www.biorxiv.org/content/10.1101/2023.04.13.536777v1.full

[jondoeuk]

Depends on the edits. The authors go on to say limited survival of transferred human NKs is due to lack of homeostatic cytokine signaling. I know some are adding IL-15/IL-15Ra complexes, but these papers show that sustained stimulation impairs cell functions https://insight.jci.org/articles/view/96219 https://www.pnas.org/doi/10.1073/pnas.1012128107

[NY1972]

Endless edits still doesn't address the infection that started the mess. Viral or bacterial
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9289786/

[NY1972]

What is the impact of multiple edits on NK longevity? Sounds like the cancer ligands are exhausting the CAR NK in PB before they get into TME.
"survival of transferred human NK cells is limited in NSG mice, and only a small number of human NK cells infiltrate lung tissue"

[jondoeuk]

Some more info on CLASH https://www.liebertpub.com/doi/10.1089/crispr.2023.0003

[jondoeuk]

The poster

[jondoeuk]

I was hoping they would have focused on solid tumours, with a number of novel CARs, including targeting MICA/B (as well as other NKG2DLs) starting in select patients who progressed on checkpoint inhibitors https://aacrjournals.org/cancerimmunolres/article/8/6/769/470218/Inhibition-of-MICA-and-MICB-Shedding-Elicits-NK

[harry crumb]

Out 6.60-6.65, $$$$$

[NY1972]

ICE that does ADCP has value. AFM 13 mono had >75% response on AITL/PTCL. No HPD as in NIVO.

[NY1972]

CAR NK looks like CART. What is the point? NK should behave like a termite. It is for the war of attrition.

[jondoeuk]

I can see why they chose the targets they did, but it makes little sense to waste resources as there are a lot of (good) therapies targeting CD19, BCMA and HER2 either approved or in development https://www.modulustherapeutics.com/pipeline

Focusing on MTX-202, Catamaran Bio are already further along with CAT-179. It is off-the-shelf, has an optimised CAR for NKs, dominant-negative TGF-B receptor and IL-15, engineered using a non-viral system https://catamaranbio.com/wp-content/uploads/2022/11/Moore_et_al._SITC_2022-poster_final.pdf

They are also working on a number of switch receptors, including https://catamaranbio.com/wp-content/uploads/2022/05/Storer_et_al._ASGCT_2022.pdf

[jondoeuk]

In this, the authors show that iPSC-derived NKs (ex vivo expanded to induce a ''memory-like'' phenotype) show stronger efficacy with TIPE2 knocked out. Also, double (TIPE2/CISH) knockout synergise together https://jitc.bmj.com/content/11/2/e006002

[jondoeuk]

From twitter

$FATE @ Barclays ($540m cap, ~$450m cash), topics:
-the CD38 knockout cell + CD38 antibody as conditioning (they should be able to compare persistence across cohorts w/ or w/ out the antibody & to their experience in NHL)
-next dose for BCMA is 1b cells 3x, want 20-25 pts, so…

— brendan (@brendan_49) March 15, 2023

[jondoeuk]

(OT) Cellinfinity Bio will leverage proprietary, directed evolution, identifying genetic modifications and CAR constructs that try to substantially improve engineered T- and NK cell function against solid tumours.

Their proprietary unbiased evolution technologies, such as CLASH may allow them to find universal modifications that can overcome poor tumour infiltration, immunosuppressive tumour microenvironment, and increase cell persistence https://www.nature.com/articles/s41587-022-01639-x

Also, they have licensed other novel technologies, including a genome-wide gain-of-function screening platform for boosting T-cell function https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00053-5

In addition, a way to edit both https://www.nature.com/articles/s41592-019-0329-7

[jondoeuk]

Preclinical data on an anti-CXCR5 CAR https://www.nature.com/articles/s41467-020-20488-3

The anti-BCMA CAR https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(18)30271-5

Also, EBAG9 https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(22)00430-0 https://insight.jci.org/articles/view/155534

[jondoeuk]

Naturally, HLA-G blocks immune cell function by binding the inhibitory receptors ILT2 and ILT4. All active isoforms of HLA-G must engage the D1 and D2 domains of ILT2 and ILT4. So, to overcome this, extracellular domains from ILT2 or ILT4 that bind with HLA-G are fused with intracellular signaling domains that activate NK cell function. NKILT's activation mechanism utilises the disulphide-linked dimerisation of HLA-G to promote CIR dimerisation and NK cell activation.

[jondoeuk]

(OT) CARTemis Therapeutics

[NY1972]

Have you seen this in gene modified NK cells study?

From AFM13 study, Shedding actually allowed NK cells performing three or more kills in sequence, including cells expressing low levels of CD30

[jondoeuk]

CAT-248, an allogeneic CD70-directed CAR-NK cell therapy effectively controls CD70-positive tumor xenografts https://www.abstractsonline.com/pp8/#!/10828/presentation/3311

CAT-179, an allogeneic NK cell product expressing HER2-CAR, IL-15 and TGFß dominant negative receptor, durably regresses HER2-expressing xenograft tumors in mice https://www.abstractsonline.com/pp8/#!/10828/presentation/3318

Genetically modified TGF-ß dominant negative receptor and IL15 enhance Natural Killer (NK) cell mediated cytolytic activity in glioblastoma https://www.abstractsonline.com/pp8/#!/10828/presentation/3057

[jondoeuk]

(OT) Catamaran Bio will use healthy donor NK cells, synthetic biology, and non-viral engineering to create novel CAR-NK cell therapies.

[jondoeuk]

Engineered iPSC-derived NK cells as next-generation immunotherapies for cancer https://www.abstractsonline.com/pp8/#!/10828/presentation/3035

A novel method for clinical scale production of natural killer cells from clonal master induced pluripotent stem cells with CISH knockout for next generation, off-the-shelf cancer immunotherapy https://www.abstractsonline.com/pp8/#!/10828/presentation/9400

Developing an allogeneic iPSC derived macrophage cell therapy for oncology https://www.abstractsonline.com/pp8/#!/10828/presentation/3344

[jondoeuk]

Identification of novel CAR transmembrane and endodomains for improved persistence and cytotoxicity of NK cell therapies https://www.abstractsonline.com/pp8/#!/10828/presentation/3324

[harry crumb]

In this at 5.00 awhile back

[harry crumb]

Whats the story behind these lawsuits? Any thoughts

[jondoeuk]

Yes, clinical data from AUTL's AUTO6* https://www.science.org/doi/10.1126/scitranslmed.abd6169

Local secretion should further enhance depth and durability. The first clinical data could come from China. I know two groups are running different trials testing either auto CAR-T or auto CAR-NK cell therapies. The former (just CD4+ T-cells) is designed to secret IL7/CCL19 and/or scFvs against PD-1/CTLA-4/TIGIT, while the latter IL7/CCL19 and/or scFvs against PD-1/CTLA-4/LAG-3.

* Moving AUTO6NG into the clinic soon

[jondoeuk]

On the 28th of this month, Q4 and full year 2022 earnings. Webcast at 5:00 PM EST https://edge.media-server.com/mmc/p/zf9z6ubw

[jondoeuk]

CT041, an auto anti-CLDN18.2 CAR-T has shown promising activity, with an ORR (across three different trials) of ~60%, in patients with gastric, gastro-esophageal junction and pancreatic cancers. However, mPFS, mDOR and mOS need improving, which is where that could come in. I know they already add nab-paclitaxel as part of the preconditioning regimen.

Also, the same company showed a synergistic effect of CAR-T with tyrosine kinase inhibitors. In the paper, sorafenib augmented effects by promoting IL-12 secretion in TAMs, as well as cancer cell apoptosis https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(19)30186-8

In addition, there is this case report https://www.frontiersin.org/articles/10.3389/fimmu.2022.963031/full

[harry crumb]

Adding to the stash

[NY1972]

This CART is great, targeting is still a big issue. GD2 for NB?
local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and should prevent systemic toxicities. This combination of CAR T cell therapy, local CD47 blockade, and orthogonal antibody may be a strategy to overcome the limitations of tumor antigen loss and heterogeneity and immunosuppression of the CAR T cell.

https://pipelinereview.com/index.php/2023020382612/DNA-RNA-and-Cells/CoImmune-Announces-Novel-Engineered-CAR-T-Cells-Improve-Anti-Tumor-Activity-and-Reverse-Immunosuppression-in-Preclinical-Models.html