jondoeuk
2週前
Historically, the criticism of NK therapies has been that they don't persist, don't expand, and don't control solid tumours. Now another paper challenges that https://www.science.org/doi/10.1126/scitranslmed.adw5567
A phase I trial of CD39+CD49a+CD103+ NKs (+/- cetuximab) in patients with advanced HNSCC is planned. The team has also developed a method for transforming and expanding the cells at scale, with one donor potentially generating around twenty doses in about two weeks.
The most important question is unlikely to be safety, but whether these cells actually infiltrate, persist, expand, and function in patients. If these NKs show activity, they may validate that cell phenotype may matter as much as the CAR and engineering.
So a future engineered iPSC-derived T-cell might not try to become a conventional circulating effector CD8+ T-cell. Instead, developers may engineer tissue-resident and stem-like programs, while preserving cytotoxicity (this would be built on with CAR(s) and other engineering). That's similar to what this NK population appears to have.
jondoeuk
3週前
I wouldn't say that CAR-T is not the long-term solution, but rather the current CAR-T's are probably not the long-term solution.
Satricabtagene autoleucel has shown CAR-T's can produce clinically meaningful benefit in at least some solid tumours. Now others are in late-stage development, including https://biopharmaapac.com/news/92/8031/oricell-advances-first-gpc3-car-t-therapy-into-confirmatory-phase-ii-trial-for-advanced-liver-cancer.html and https://www.globenewswire.com/news-release/2026/06/08/3307886/0/en/Lyell-Immunopharma-Provides-Update-on-Safety-Profile-of-LYL273-in-Relapsed-or-Refractory-Metastatic-Colorectal-Cancer-and-Amends-Phase-1-Trial-to-Phase-1-2-Expansion.html
As for FT836, if it eventually shows modest ORRs in some indications, but prolonged disease stabilisation, and improved OS, it could still win out.
jondoeuk
4週前
Based on the slides, NT-175 looks interesting. The slide that jumps out is in metastatic pancreatic ductal adenocarcinoma. Even with the very few patients treated, seeing multiple responses is noteworthy. Historically, that type has been one of the most difficult solid tumours for any therapy.
The ORR, DCR, (m)PFS, (m)DoR, and the fact that some responses appear ongoing is encouraging.
As for the failures, a lot barriers still remain even when persistence is largely solved. That is the kind of information that can often result in next generation versions.
A know a new version will add a CD8 co-receptor into CD4+ T-cells and knockout CBL-B as well https://aacrjournals.org/cancerres/article/85/8_Supplement_1/3478/758580/Abstract-3478-Pre-clinical-characterization-of https://jitc.bmj.com/content/13/Suppl_2/A396 https://clinicaltrials.gov/study/NCT06218914
Going forward, it should be possible for them to insert a single multifunctional DNA cassette into the TRAC locus with manufacturing improvements. For the former, they could add an optimised TCR, CD8 co-receptor (+/- co-stim domain(s)), cytokine signal(s), and additional modifications, such as shRNA to knockdown CBL-B and TGFRB2.
jondoeuk
4週前
So far, so good. Eligibility required R/R disease, and at least three prior lines of therapy, including a proteosome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb. All patients achieved a response, and responses deepened over time. The one patient with extramedullary disease showed complete resolution by month one. A lymphoma candidate is already in the works. I wouldn't be surprised if they expand to autoimmune diseases as well.
For solid tumours, I know of at least three companies developing ''armoured'' in vivo CAR-T therapies, including Waypoint Bio, which is leading the pack.
As for off-targets, still too early to say.
jondoeuk
4週前
So far, a mixed bag. At future updates I'd want to see mono, paclitaxel-containing regimens, more KRASwt MSS mCRC patients, and patients with liver mets. Also, are any reductions/responses transient or durable. In addition, Day-22 biopsy analyses.
Adding lymphodepletion (despite the entire premise that it is not needed) chemo could improve the expansion and persistence of FT836 by creating "space" and reducing competition for homeostatic cytokines. The question remains if and how much efficacy is being sacrificed to avoid lymphodepletion. It would be easier to add conditioning later than to convince doctors and patients to accept conditioning if they demonstrate activity without it.
There are also rational adjuncts, including low-dose 5-FU, low-dose radiotherapy, low-dose panobinostat, and low-dose celecoxib. At least two of these would be straightforward clinically.
NY1972
4週前
BCMA TCE, biAb were great in MM too. Works great on plasma cell depletion. But SLE is not cancer, it is germinal centers driven by Tfh and LLPC. Invivo will be useless in solid cancers where T cells are suppressed, TCE, biAb, ADC are all useless. What is the chance of 0ff target editing that creates leukemic T cells?
jondoeuk
4週前
The CD58 KO is one of the more differentiated aspects of what Fate is doing, while CD16A with the mAb has a clear rationale.
As for CAR design, Fate developed an AvER, which improved antitumour activity https://jitc.bmj.com/content/12/Suppl_2/A355
Also, AI/ML models can analyse data from massive high-throughput screens to predict how combinations will affect cell function, cytotoxicity, and persistence https://www.science.org/doi/10.1126/science.abq0225
Platforms like CAR-Toner have been developed as well https://communities.springernature.com/posts/harnessing-ai-to-refine-the-future-of-car-t-therapy-insights-behind-the-development-of-car-toner
The really interesting future is not just using AI/ML to optimise CARs, but optimising the entire engineered cell and phenotype for different cancers.
jondoeuk
1月前
Thanks. For this trial, the primary endpoint is CRR (at week 26), which requires UPCR, eGFR, and no rescue therapy.
Based on the data so far, it suggests some patients achieve deep renal responses (that would be CRR), while the cohort overall showed broad renal improvement. It will be interesting to see the EULAR data looking at reproducibility across the cohort.
jondoeuk
1月前
The CEO, Dr. Wang, disclosed for the first time that the dual-target CAR-iNK product NEUK203-215 for autoimmune diseases has enrolled seven patients with no SAEs to date, and all patients showed a successful immune reset in the peripheral blood. Except for the first low-dose patient whose response was close to the target, other patients treated with medium to high doses achieved or exceeded the present endpoints within up to three months.
Another CAR-iNK product for DLL3+ solid tumours, NEUK203-13, has been tested in the first patient, who demonstrated a good safety and tolerability profile. In addition, iPSC-derived iT and iMSC products have completed the development and validation of editing and manufacturing processes, progressing to preclinical evaluation.
They have also initiated in vivo CAR tech and product development, with early proof-of-concept for proprietary CD7 antibody-conjugated tLNP-specific delivery platforms.
jondoeuk
1月前
Waypoint Bio has raised $20 million in a Series A financing to test multiple cell therapies in China.
They plan at least three IITs in China with this new funding round, which comes on top of an initial raise of $14.5 million https://www.businesswire.com/news/home/20240628087950/en/Waypoint-Bio-Launches-with-%2414.5M-to-Turbocharge-Drug-Discovery-using-in-vivo-Spatial-Pooled-Screening-Technology
Two of the CAR-T cell programs (both ex vivo and in vivo) will target Claudin 18.2 in gastric, GE junction and/or pancreatic cancers, and should begin by the end of the year. A third (in vivo) for CRC and prostate will be tested at a later date.
One armouring strategy it will use is a novel synthetic protein that boosts the infiltration of T-cells into tumours and, once inside, increases the proliferation and cytotoxicity.
Preclinical data https://aacrjournals.org/cancerres/article/84/6_Supplement/6329/735626/Abstract-6329-Pooled-in-vivo-screening-of-hundreds https://jitc.bmj.com/content/12/Suppl_2/A382 https://aacrjournals.org/cancerres/article/85/8_Supplement_1/3181/757112/Abstract-3181-Single-cell-characterization-and https://jitc.bmj.com/content/13/Suppl_2/A265
jondoeuk
1月前
Newer work from the U of M suggests that transcriptional programming can improve iNK function https://academic.oup.com/jimmunol/article-abstract/214/11/2961/8239067
Also, the ''best'' engineered products may need to build on an tissue-resident adaptive phenotype, not bulk NKs. Again, recent data from the U of M https://aacrjournals.org/cancerimmunolres/article/doi/10.1158/2326-6066.CIR-25-1229/784908/Integrated-Single-Cell-Profiling-Reveals
The tissue-resident adaptive NKs were the only subset (out of six) that demonstrated consistent, robust associations with improved survival across different primary, therapy-naïve and metastatic solid tumours, and in response to checkpoint blockade. Notably, elevated infiltration of these NKs was more prognostic than high tumour mutational burden in certain types treated with checkpoint blockade. Additionally, these NKs were strongly correlated to the infiltration of CD8+ T-cells and B-cells in tumours. Interestingly, paired pre- and post- checkpoint blockade treated tumours revealed expansion of cytotoxic tissue-resident adaptive NKs after treatment.
jondoeuk
1月前
If true (about all nine), that would matter because the early efficacy signals could mostly reflect combination activity, not FT836 monotherapy, so it becomes harder to infer whether FT836 alone contributes meaningfully.
As for LD chemo and RT, true, but the current protocol has a number of arms, including with paclitaxel, which suggests they think tumour/TME preparation may matter.
Also, the HER2 arms may exist because of different populations and a broader commercial opportunity.
jondoeuk
1月前
Opening this trial suggests continued institutional confidence in the broader platform and safety profile, but for an academic trial it looks unusually conservative looking at the number they plan to enrol and the (primary) endpoint. As for the exclusion criteria (prior bevacizumab or cellular therapy), it could reflect concerns around immune effects, confounding interpretation, wound healing, and/or edema.
I think the trials (including another in recurrent ovarian, fallopian tube, and primary peritoneal cancers also using FT536) will feed directly back into the next-gen iPSC engineering strategy that the U of M has a number of grants for like this https://reporter.nih.gov/search/d9lW8yEhyEKJeSffPzNN6Q/project-details/11158564
jondoeuk
1月前
''Results:
First three pts (all MSS mCRC; median: age 45 y, prior therapies of 5, disease duration of 51 months) were treated in Regimen C dose level 1 (DL1 = 300 million cells/dose, Days 1 and 15 with cetuximab, no CCT) and completed dose limiting toxicity (DLT) evaluation (data cut-off 15 JAN 2026) with no DLTs, FT836-related serious adverse events, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) reported. One of the three pts demonstrated a CEA response with >50% reduction (480 ng/mL at BL; 230 ng/mL at 4 weeks after first FT836 infusion) that correlated to mass shrinkage in all target lesions in a week 7 CT scan (obtained after data cut-off date). Of the other two pts, one experienced PD while the other was not yet assessed at the time of abstract submission.
FT836 was detected in peripheral blood (PB) following the first dose, with persistence observed up to 1 week. Notably, FT836 cells were detected beyond the initial PB detection in a tumor biopsy obtained at Day 22 (±3 days) indicating greater persistence in tissue compared to PB, supporting the value of additional engineered elements. EGFR and MICA/B antigens were identified in 3/3 baseline tumor biopsies, highlighting the relevance of multi-antigen targeting in driving patient outcome.''
jondoeuk
2月前
Early pharmacodynamic evidence across three different trials in China (two in autoimmune* and one in haematological malignancies) show that in vivo mRNA CAR approaches can induce systemic CD19+ B-cell depletion across compartments (blood, LN, and/or BM), but still without sufficient numbers to determine safety, durability, and long-term clinical benefit.
* Being presented at the upcoming ASGCT conference.
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