[NY1972]

The key to success is CXCR2 and 1xx for FATE CART. MSK 1xx CD19 auto trial showed ORR at 25M cells dose, so trogocytosis, persistence and proliferation must be optimal to be effective.

[jondoeuk]

One of the potential downsides of inhibiting (CD16(a)) shedding is that it could slow NK detachment and reduce serial killing https://rupress.org/jcb/article/217/9/3267/120862/Shedding-of-CD16-disassembles-the-NK-cell-immune

It was shown some years ago that CD64 binds to the same IgGs, but with at least 2-3 orders of magnitude higher affinity than CD16(a). Based on that data, I think they should switch to using it and look to add additional modifications https://jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01455-z

They (and others) need to learn from the (early) mistakes of FATE.

[jondoeuk]

Trogocytosis can impact both CAR-T, as well as CAR-NK therapies. Strategies to overcome trogocytosis-induced antigen loss, fratricide and/or cell exhaustion include, pharmacological targeting, modulating CAR affinity, ''armouring,'' modulating the signalling domain(s), or using a dual CAR strategy. Some preclinical data on the latter https://www.nature.com/articles/s41591-022-02003-x

[NY1972]

The functional effects of trogocytosis remain to be elucidated, however, it has been shown to interfere with successful CAR-mediated antitumor responses as it promotes tumor antigen escape as well as CAR T cell dysfunction due to fratricide killing
https://jitc.bmj.com/content/11/2/e005691

[NY1972]

This study was done without ADCC.

expression of CXCR2 in CAR-T cells can significantly improve these T cell migrating to the tumor microenvironment of hepatocellular carcinoma, which provides the strong evidence to support that CXCR2 is of great potential to be utilized in CAR-T cell therapies for various solid tumors.

https://onlinelibrary.wiley.com/doi/full/10.1002/eji.201948457?utm_source=chatgpt.com

[jondoeuk]

Both follow LD chemo in Cycle 1 (each cycle is approximately 61 days). Based on the safety, tolerability, and radiographically confirmed clinical benefit to treatment (in Cycle 1), participants may be considered for an additional treatment cycle (Cycle 2 retreatment).

[jondoeuk]

NEUK201-00* is being tested in advanced/metastatic solid tumours at a single site.



* It could be an iNK with just a high-affinity non-cleavable CD16(a) receptor, but this comes from a Chinese site that has undergone translation. The IL-2 dose is intermediate.

[NY1972]

ADCC will lead to higher expression of CXCL8 by innate cells which will lead to more FT825 into TME. The combo trial will be a game changer. What is the dosing schedule for cetuximab?

[jondoeuk]

Translational data from the PhI B-cell lymphomas trial demonstrated primary, secondary and tertiary tissue trafficking and clearance of CD19+ cells. That should help enable an immune reset in autoimmune diseases.

The next-gen CAR-T's will incorporate a suite of novel synthetic edits that are designed to enhance homing and biodistribution to secondary and tertiary tissues.

[jondoeuk]

I hope they will pick up the pace with enrolment. It can't be as slow as last year.

[jondoeuk]

Shoreline has let go of an undisclosed number of employees tied to a cell therapy project with GILD's Kite Pharma, Endpoints News reported. Shoreline CEO declined to disclose the number of workers that were laid off and said the future of the collaboration is still ''to be determined.''

The two had agreed to change the focus of their partnership. Instead of developing a CAR-iNK cell therapy for B-cell lymphomas (either CD19-targeted or CD19/CD20-targeted), they switched to autoimmune diseases. Shoreline already had a pre-IND meeting with the FDA and was recruiting US and international clinical trial sites for a PhI trial in autoimmune diseases. They were going to enter the clinic in the coming months and planned to give Kite the possibility of opting in after concluding the trial.

As Kite went through leadership changes in recent years, Shoreline's CEO said the two had a ''wonderful collaboration,'' including being aligned with the new [autoimmune] focus for that therapy. They agreed on ''90%'' of the terms in an adjusted deal, including another potential equity investment from GILD, but they couldn't come to an agreement on any ''back-end economics.'' Shoreline believed it deserved a ''larger portion on [the] upside.''

[NY1972]

Pipe valued at 10% of paid in capital. A CART that follows the chemotactic gradient to TME is free today.

[NY1972]

Ft825 - 4 more sites added

[NY1972]

FT819 can act as a ligand sink and change DC/CD8, NLR ratios in 2nd lymphoid and inflammed tissues. Creating a new Bronx so to speak.

CXCR4 is critical for the organization of secondary lymphoid tissues, such as lymph nodes and spleen, where immune responses are initiated.
Dysregulation of CXCR4 signaling may contribute to abnormal germinal center reactions and the development of autoreactive immune cells.

[jondoeuk]

Maybe they thought that better penetration into the bone marrow could allow for greater effectiveness in targeting certain types, such as B-ALL. CXCR4 is critical for bone marrow homing of T-cells https://onlinelibrary.wiley.com/doi/10.1002/eji.201747438 https://journals.aai.org/jimmunol/article/193/3/1013/108777/Cutting-Edge-CXCR4-Is-Critical-for-CD8-Memory-T

I know they have a patent for hematopoietic stem or progenitor cells being contacted with an agent that increases CXCR4 gene expression in the cells.

However, the iTs (that are either contacted with that agent or not) express high levels of Fas https://www.jci.org/articles/view/121491 https://www.nature.com/articles/s41467-017-00784-1 https://www.nature.com/articles/nm.3541

To overcome it, this was created https://aacrjournals.org/cancerres/article/84/6_Supplement/3995/740628/Abstract-3995-A-novel-chimeric-Fas-signal-redirect

[NY1972]

Why FT819 has high CXCR4 expression?

[NY1972]

Rearranging the deck.
Follicular structures were disrupted and FDCs were depleted in the lymph nodes after CD19-CAR T-cell therapy, but not after RTX
Let see if FT825 can do the same with LD and Cetuximab.
https://ard.bmj.com/content/annrheumdis/early/2024/09/11/ard-2024-226142.full.pdf

[NY1972]

The key is in CART and neutrophil interactions within the draining lymph nodes. Neutrophils build TME and suppress CD8+ /NK via Treg. For the primary tumor, CART will need mAb to deal with antigen escape.

https://aacrjournals.org/cancerrescommun/article/4/2/588/734969/Characterizing-Neutrophil-Subtypes-in-Cancer-Using

[jondoeuk]

I want to say one of two, but can't remember off the top of my head.

[jondoeuk]

Metastatic cancer cells can develop multiple (suppressive) mechanisms that enable the evasion of NKs, such as this https://www.cell.com/cell-reports/fulltext/S2211-1247(24)01206-3

In one patent the same group goes on to show that EP2/EP4 KO enables the NKs to secrete chemokines, such as XCL1 that recruit key immune cell populations required for T-cell mediated tumour immunity https://www.cell.com/cell/fulltext/S0092-8674(18)30039-4

In another paper, a different group identifies IGSF8 as a new immune checkpoint that suppresses NKs (and dendritic cells) in antigen presentation deficient cancer cells https://www.cell.com/cell/abstract/S0092-8674(24)00355-6

So I think the right combination of edits will be needed to overcome trafficking, infiltration, potency, expansion, persistence, while also preventing exhaustion/dysfunction, suppression, tackle antigen heterogeneity and evasion.

[NY1972]

Which other bios have CART with CXCR2? That feature is critical after lymphodepletion causing BM suppression for 2 weeks.

[NY1972]

Sounds like what one would find in SLE, cancer pts with a reset immune system.

?d T-cell proliferation was dependent upon CD137L expression on aAPC and addition of exogenous IL2 and IL21. Propagated ?d T cells were polyclonal

[jondoeuk]

For many, many years the focus was on the Vd2 subset, but recent evidence in multiple tumours showed associations of other subsets (Vd1 and/or Vd3) with increased patient survival and/or clinical benefit https://www.nature.com/articles/s43018-022-00376-z https://www.science.org/doi/10.1126/scitranslmed.aax9364

There is also preclinical data which show that the Vd1 subset has superior cytotoxicity over Vd2 https://aacrjournals.org/clincancerres/article/20/22/5708/117332/Activating-and-Propagating-Polyclonal-Gamma-Delta

[NY1972]

NK is fine for SLE since the depletion of the memory B cells is the goal. For solid, creating polyclonal T cells with memory phenotype is the key for OR duration.
From ChatGPT:
Studies with 1XX CAR T cells highlight their enhanced capacity for cytokine production and survival, suggesting a stronger potential for interaction with and modulation of DCs compared to conventional CAR T cells. Dendritic cells in the TME can process these antigens and cross-prime endogenous T cells against TAAs, creating a polyclonal immune response that complements the CAR T-cell activity.

[jondoeuk]

They should get a B7-H3 CAR into the clinic https://www.oncologypipeline.com/apexonco/fourth-challenger-dualitybio-and-biontech

Based on preclinical data targeting the IgC domain is more effective https://www.nature.com/articles/s41467-023-41631-w

[jondoeuk]

Unlike NKs, the differentiation of T-cells from iPSCs is (far) more complex. Also, the NKs from iPSCs are more comparable functionality to PB/CB NKs, and can kill independent from the CAR.

It would make sense to test the two https://aacrjournals.org/cancerimmunolres/article/7/3/363/469550/NK-Cells-Expressing-a-Chimeric-Activating-Receptor

But there are still hurdlers (for the NKs) to overcome, including persistence and lack of expansion. The use of an IL15-RF may impair NK functions as well https://insight.jci.org/articles/view/96219 https://www.pnas.org/doi/10.1073/pnas.1012128107

[NY1972]

1xx, autologous T cells and lactate
https://pmc.ncbi.nlm.nih.gov/articles/PMC11588660/

[NY1972]

SP from 100 to 1 while revamped pipeline from 1 to 100

[NY1972]

CEO was pretty bullish on 825 + cetuximab. I think Ig1 is as effective as TCE as it activates the innate arm.

[jondoeuk]

FT825 would require an additional receptor https://ashpublications.org/blood/article/140/Supplement%201/7429/491146/A-CD3-Fusion-Receptor-CD3-FR-Uniquely-Enables

[NY1972]

Failure to revive old cells
https://www.merck.com/news/merck-provides-update-on-keyvibe-and-keyform-clinical-development-programs-evaluating-investigational-vibostolimab-and-favezelimab-fixed-dose-combinations-with-pembrolizumab/

[NY1972]

FATE revamped it's cell to deal with TME. Yet the SP is 1.8% of what it used to be. 95% investors were in it for ride because J&J was on board. They had little understanding of science.

[NY1972]

Why bother with CARNK after they licensed 1xx from MSK. CAR T 1xx lowers the activation and energy req'd to survive in the hypoxic TME. More durable and lower CRS CART therapy will beat ADC in terms of AE and OS long term.

[jondoeuk]

Hard to say. After the termination of a 2020 collaboration agreement with Johnson & Johnson's subsidiary Janssen, FATE slashed its pipeline, including FT536, FT516, FT596 and FT538.

[NY1972]

The combination of p95HER2.CAR T cells and HER2?x?CD3 bispecific antibodies lead to a complete regression in three HER2-positive, patient-derived mouse xenografts tumor models
https://pmc.ncbi.nlm.nih.gov/articles/PMC11574131/

[NY1972]

So they abandoned FT536 after looking at PK in 6 pts.

[jondoeuk]

I am looking for some FT536 P1 data to figure out why they decided on 3 day dosing at U of M?

Either based on data from other trials and/or the biology of NKs (they do not typically expand upon encounter with antigen and lack long-term persistence). It looks to be a compressed dosing schedule, which could extend exposure and increase Cmax levels.

That poster only listed 3 pts dosed at 100M cells mono, how about higher dosages?

Monotherapy escalation was continuing at 300 million cells/dose. So I assume (rightly or wrongly) that those two patients had been treated at this dose level. From memory, they were going to test at least a third dose level as well (500 million cells/dose). Also, had an option to add IL-2 once the MTD had been reached.

[NY1972]

I am looking for some FT536 P1 data to figure out why they decided on 3 day dosing at U of M? That poster only listed 3 pts dosed at 100M cells mono, how about higher dosages?

[jondoeuk]

They presented initial data at SITC '22 (another two were enrolled before it was terminated) https://fatetherapeutics.com/wp-content/uploads/2022/11/SITC2022_FT536_FinalDraft-VFINAL.pdf

Another trial (not sponsored by FATE) is ongoing https://clinicaltrials.gov/study/NCT06342986

[jondoeuk]

A number of biotechs were hit (hard) this week.

[NY1972]

Have you seen the clinical data from FT536 P1?