Another update https://www.globenewswire.com/news-release/2024/12/12/2996508/0/en/Editas-Medicine-Announces-Strategic-Transition-to-in-vivo-Gene-Editing-Company-with-Intent-to-Achieve-Human-Proof-of-Concept-in-Approximately-Two-Years.html

Any target they go after will likely have multiple players (far) ahead them (and some using better delivery and/or editing tech).

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

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

The news https://www.globenewswire.com/news-release/2024/12/09/2994080/24675/en/Fate-Therapeutics-Presents-New-Phase-1-Clinical-Data-of-FT819-Off-the-shelf-CAR-T-cell-Product-Candidate-for-Systemic-Lupus-Erythematosus.html

Hopefully, another (small) pop tomorrow based on the latest news.

The PR https://www.globenewswire.com/news-release/2024/12/09/2993974/0/en/CRISPR-Therapeutics-Presents-Data-at-the-2024-American-Society-of-Hematology-ASH-Annual-Meeting.html

Poster https://ir.crisprtx.com/static-files/12114290-21a6-4544-9cb7-de4fe2852e94

For oncology, it will be put on the back burner.

Turns out a few companies screened a CAR panel, including CD3 family, ITAM silent, etc. So it could be possible. As for gd-T cells, results from one group indicated that igd-T cells have differences when compared to PB-derived gd-T cells https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(23)00057-7

Different subsets are important for activity https://www.nature.com/articles/s41586-022-05593-1

A phase 2 trial, PANOVA-4, will test TTFields combined with a triplet regimen of gemcitabine, nab-paclitaxel and atezolizumab as a first-line treatment for metastatic pancreatic ductal adenocarcinoma. It has completed enrolment and the company said it expects to have data in 2026.

The primary endpoint is disease control rate (DCR). Secondary endpoints include, overall survival (OS), progression-free survival (PFS), 1-year OS rate, objective response rate (ORR), PFS at 6 months, duration of response, and safety.

The PR https://www.globenewswire.com/news-release/2024/12/02/2989665/0/en/Senti-Bio-Announces-Positive-Initial-Clinical-Data-in-Phase-1-Clinical-Trial-of-SENTI-202-a-Logic-Gated-Selective-CD33-FLT3-Targeting-CAR-NK-Cell-Therapy-for-the-Treatment-of-Relap.html

Webcast (Dec 3, 7:30 AM EST) https://edge.media-server.com/mmc/p/q37k42qa/

Novocure plans to file for regulatory approval in the U.S., EU, Japan and other key markets; Zai Lab plans to file for regulatory approval in China https://www.businesswire.com/news/home/20241202363277/en/Zai-Lab-and-Novocure-Announce-Positive-Topline-Results-from-Phase-3-PANOVA-3-Clinical-Trial-of-Tumor-Treating-Fields-TTFields-Therapy-for-Pancreatic-Cancer

TScan I. They created a library of 2,439 TCRs derived from the lesions of thirteen melanoma patients. The T-cell pool was co-cultured with melanoma cell lines that had matched HLAs and a normal cell line was used for the control. Ninety-five TCRs were identified in the high-throughput screen and selected for validation. Forty-eight were validated when tested individually. Twenty-one were successfully deorphanised and found to target therapeutically relevant shared antigens, including MLANA* and Tyrosinase. This approach will be expanded to other cancer indications to allow for the discovery of new targets.

* A trial testing a TCR (plus vaccination) against this showed activity https://aacrjournals.org/clincancerres/article/20/9/2457/78907/Adoptive-Transfer-of-MART-1-T-Cell-Receptor

They now add an investigational HIV vaccine to its portfolio https://www.fiercebiotech.com/biotech/gilead-buys-hiv-vaccine-spanish-biotech-following-success-clinical-collab

Data on the vaccine in combination with vesatolimod https://www.ddw-online.com/hiv-combination-regimen-could-lead-to-viral-remission-22215-202302/

Based on recent data*, I would have thought that getting KITE-509 into the clinic (for GPC3+ solid tumours, not just 3L+ HCC) would be a priority.

* https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4019 https://www.nature.com/articles/s41586-024-08261-8

CTX130 data in R/R T-cell lymphomas (peripheral T-cell lymphoma or cutaneous T-cell lymphoma) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(24)00508-4/abstract

The ORR was 46.2%. Of those treated at DL3 and higher, the ORR was 51.6%.

As said, Lyfgenia is the value driver for the company https://insights.citeline.com/pink-sheet/advanced-technologies/cell-and-gene-therapies/gene-therapy-lyfgenia-voucher-denial-puts-sickle-cell-treatment-at-risk-bluebird-bio-says-P6K4SEA2AFDKDF5SZZNZPBH4YM/

Did managing have no communication with the agency? I find that hard to believe, well maybe not when you take into account who runs the company! Their cost cutting measures came too late as well.

Dr. Huntington is the CSO. From this https://acir.org/weekly-digests/2024/november/sitc-39th-annual-meeting-2024#2;

''A 2008 NCI survey identified IL-15 as one of the top cytokines for potential immunotherapy, and multiple subsequent studies have demonstrated a critical role for IL-15 in multiple immune cell types. Further, direct and correlative data have linked IL-15 to good outcomes in animals and humans. Nonetheless, IL-15R agonists have failed in the clinic due to severe toxicity.

Spurred on by this challenge, Nicholas Huntington focused on how to target the signaling-induced inhibitory pathway, reasoning that although IL-15R is widespread throughout the body, IL-15 levels are very low in healthy tissue (but high in tumors) and that by preventing receptor degradation, cells would be hyperresponsive to the IL-15 produced in the tumor and not activated systemically. A CRISPR knockout screen in human NK cells under conditions of low IL-15 identified a number of genes (UBE2F, ARIH2, CISH, CUL5, RNF7, DCUN1D3, UBE2L3, ELOC), whose elimination allowed better NK cell growth.

All these genes were involved in protein homeostasis affecting neddylation and subsequent ubiquitination, leading to degradation. Functionally validating these results, individual knockouts of these genes in NK cells and the NK-92 cell line enhanced proliferation, cytokine production, and metabolic features of the NK cells, and the expected upregulation of IL-15R surface detection. Importantly, an inhibitor of pan-neddylation phenocopied the effects of UBE2F-gene knockouts, supporting that the pathway could be targeted for therapy.

Serial cytotoxicity studies with gene knockouts in NK cells or CAR NK cells demonstrated robust serial killing, indicating the cells were metabolically very fit and resistant to exhaustion, which translated to enhanced control of MHC-I-expressing or -deficient tumors in syngeneic mouse models. The unexpected observation of activity against MHC-I-expressing tumors was a direct effect of CD8+ T cells, but enhanced by hyperactive NK-mediated improvements to the T cell response. Most of the identified gene targets were part of a degradative pathway; some could be deleted with minimal effects, and so were non-essential. Importantly, some of these targets were enzymes, setting up the opportunity to identify small molecular inhibitors specific to this class of drug targets.''

A number of companies have licensed it. Based on new data is seems that there is no one-size-fits-all, so pooled screening of different CARs to try and find the best for specific types will be needed https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(23)00495-1

The FDA said it is look­ing in­to the ''known risk'' and as­sess­ing po­ten­tial ''fur­ther reg­u­la­to­ry ac­tion.'' https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-hematologic-malignancy-following-skysona-elivaldogene-autotemcel

Along­side the Oc­to­ber NE­JM ar­ti­cle was an ed­i­to­r­i­al from an US NIH haematologist who said more cas­es might ap­pear over time https://www.nejm.org/doi/full/10.1056/NEJMe2409399

A post on LinkedIn (by Alex Shih-Min Huang who is VP, Head of Cell Therapy at BGNE): ''Though our very first experiment was initiated only 2.5 years ago amidst ongoing laboratory construction and pandemic, fast forward to this day, we have already 1) generated a proprietary, well-characterized GMP grade iPSC clone collection designated for our future gd T and ab T cellular products, 2) established our unique efficient, enrichment-free, feeder-free methodologies that deliver impressively high purity and high expansion fold for our iPSC derived gd T and iPSC derived CD8 ab T platforms, and 3) engineered proprietary genetic elements that further enhance the longevity and potential efficacy of our effector cell populations. Our platforms are designed to allow plug-and-play for a variety of CAR-T and TCR-T cell therapies with potential to address unmet needs in diverse indications.''

One for FT819 as well https://www.globenewswire.com/news-release/2024/11/18/2982757/24675/en/Fate-Therapeutics-Presents-6-Month-Follow-up-Data-on-First-Patient-Treated-in-Phase-1-Autoimmunity-Study-with-Fludarabine-free-Conditioning-and-FT819-Off-the-shelf-1XX-CAR-T-cell-P.html

The PR https://www.globenewswire.com/news-release/2024/11/18/2982736/24675/en/Fate-Therapeutics-Highlights-FT522-Off-the-shelf-ADR-armed-CAR-NK-Cell-Product-Candidate-at-2024-ACR-Convergence.html

They need to pick up the pace of enrolment. If they don't see activity at DL2, I think it could be in trouble.

Big volume into the close, over 12 million. Someone knows something.

This will be interesting, but we know that cancer cells are able to develop multiple mechanisms that enable the evasion of NKs. These mechanisms are likely the reason why NK based therapies show only limited success in clinic trials. Here is just one mechanism (that was recently found) https://www.cell.com/cell/abstract/S0092-8674(24)00355-6

https://x.com/DrPatSoonShiong/status/1861433583186932141

A new paper on anti-HER2 CAR-NKs (+/- anti-PD-1) https://academic.oup.com/neuro-oncology/article/26/Supplement_8/viii85/7890050

One wonders if they were desperate after the latest TIGIT blow-up (and based on the partnership they already had) https://www.fiercebiotech.com/biotech/roches-tigit-prospect-fails-another-phase-3-lung-cancer-test

Either way I'm not complaining.

Still early, but based on the data, and the fact that BMY abandoned IMA401, it isn't a great vote of confidence in their bispecific platform https://markets.businessinsider.com/news/stocks/immatics-announces-clinical-data-on-tcer-ima402-targeting-prame-1034031315

Some slides

Not only for that, but there is evidence that it could modulate the TME (promote M1 polarisation of macrophages and/or reduce stromal density) and upregulate CXCL8 (CXCR2 is its ligand), which could increase trafficking.

Looks like Shoreline has pivoted (yet again) to autoimmune https://themalaysianreserve.com/2024/11/16/shoreline-biosciences-to-present-at-2024-stifel-healthcare-conference/

In vivo now (for some reason) https://www.biorxiv.org/content/10.1101/2024.11.06.621821v1.full

Hopefully, they will use their iPSC platform to test it.

They are working on at least three cell therapies, two of which are auto CAR-T's. For the first, they will utilise their knock-in/knock-out protocol to introduce the CAR and gene modification(s) precisely at the TRAC locus to generate four anti-HER2 CARs: PRODH2 OE [1], PRDM1 KO [2], PRODH2 OE plus PRDM1 KO, and control. If successful, this study will identify the best performing and provide sufficient data to support a path towards an IND.

The second CAR will target ENPP3 (data from another group [3]). Again, they will utilise their knock-in/knock-out protocol to introduce the CAR and gene modification(s) precisely at the TRAC locus to generate four anti-ENPP3 CARs: CTLA-4 tail fusion [4], PRDM1 KO, CTLA-4 tail fusion plus PRDM1 KO, and control. If successful, this study will identify the best performing and provide sufficient data to support a path towards an IND.

Refs:
1 https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00053-5
2 https://www.nature.com/articles/s41587-022-01639-x
3 https://aacrjournals.org/clincancerres/article/22/8/1989/265987/AGS16F-Is-a-Novel-Antibody-Drug-Conjugate-Directed
4 https://www.nature.com/articles/s41590-023-01571-5

They now have the ability to put in eight to nine edits. So it is a single cassette that expresses the CAR, can express a cytokine and has an shRNA-like approach to knock down genes. So there's no theoretical limit as to the number of edits, but there may be marginal utility beyond a certain point.

Hopefully, they look to improve donor selection, cell selection and manufacturing, as all could increase efficacy.

I think they should amend the IND to test higher doses (over 1B), enhance LD, and add nab-paclitaxel.



Data from an auto anti-HER2 CAR-T in STS https://www.nature.com/articles/s43018-024-00749-6

It could be the cut-off date and wanting to report at least some data at the right conference.

It has been https://www.nature.com/articles/s41577-024-01022-8

Q3 financial results and business updates https://www.globenewswire.com/news-release/2024/11/12/2979634/0/en/Fate-Therapeutics-Reports-Third-Quarter-2024-Financial-Results-and-Business-Updates.html

The ADR selective targets 4-1BB+ alloreactive immune cells, but it's possible that there are other alloreactive immune cells that don't express 4-1BB, so the additional KOs would allow for passive evasion (by blocking host immune cell detection and interaction).