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Patience, loading shares now is money! $$$$$
Setting up like a dream.
Need volume to send her into orbit
With all the PD1 combos failures, pharmas are going back to poisoning cancers with hundreds ADC. No survival benefits but lots AEs for the longer PFS.
Immune cells are acting like bios traders, stocking up on PD-L1 when the body is inflammed. Tumors are exploiting this habit and makes tons of PD-L1 for their consumption. Repeated admin of Chemos just create more DNA damaged cells to further promote this process.
they call me D’Angelo Russell cuz I’m #loading
Trogocytosis has been documented for other leukocytes, including T-cells. In this paper, CAR-T cells were also shown to exhibit it when co-cultured with different types of cancer cells, including CARs that used the high-affinity CD19 binding domain FMC63 (most CAR-T therapies use it) https://www.nature.com/articles/s41586-019-1054-1
Similarly, it can be triggered by engagement of the CD16 receptor on NKs with mAbs leading to reduced efficacy https://ashpublications.org/blood/article/125/5/762/34055/Fc-receptor-mediated-trogocytosis-impacts-mAb https://aacrjournals.org/clincancerres/article/22/21/5211/79645/Checkpoint-Inhibition-of-KIR2D-with-the-Monoclonal
In this, they investigated if it contributed to (anti-CD19) CAR-NK cell fratricide and tumour progression in patients with lymphoid malignancies treated in a previously reported trial https://www.nature.com/articles/s41591-022-02003-x
Using blood samples collected at multiple time points after CAR-NK cell infusion, patients were divided into two groups based on the overall trogocytosis expression on CAR-NK cells [high (n=4) vs. low (n=7)]. It was found that acquisition of trogocytosised CD19 expression on CAR-NK cells was associated with a reduction in CD19 expression on B-cells and a higher probability of relapse (3 of 4 patients) compared to patients in the low group (0 of 7 patients). Also, expression was associated with improved clinical response. Those with a lower level had improved responses (100% ORR vs. 25% ORR).
They hypothesised that an inhibitory CAR, which incorporated an scFv directed to an NK-specific antigen linked to a inhibitory signal might overcome it. To determine that, they synthesised a CAR that recognised an NK self antigen. This was done by fusing the transmembrane and intracellular domains of a CAR with an scFv targeting CS1, a co-receptor that is expressed on all normal NKs, but absent on most CD19+ lymphoid-derived malignancies.
While this did not impact the extent of trogocytosis, they observed less trogocytosis-mediated in vivo fratricide (NK self killing), as evidenced by the better cell viability, higher persistence and improved effector functions compared with control groups.
So, companies should be able to address it, but I'm not aware of any that currently are.
Gene editing T cells turning CART into ADC. Without tackling innate immunity that is pro tumor, all TCR, CART, CARNK are bound to fail.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886129/
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.
FATE's combined CD54 and CD58 genetic ablation https://www.biorxiv.org/content/10.1101/2023.10.09.557143v1
Knockout of siglec-5 and siglec-10 on macrophages https://www.pnas.org/doi/10.1073/pnas.2300366120
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.
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.
An update on the litigation proceedings against Shoreline Biosciences https://www.briefing.com/in-depth-analysis/content/article?ArticleId=IN20230905060647FATE
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.
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.
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
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
Why has AFMD had to go back to zero for LuminICE-203?
A lot of old CARs will be abandoned on the road. CARs sold by Wall St.
(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
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
(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/
(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
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
— Vivek Subbiah, MD (@VivekSubbiah) June 11, 2023
-->Started working with 1st gen DR5 targeting Rx in 2012
--> FINALLY we have a 3rd… pic.twitter.com/ksTOFdMkVr
I like the LD before CBNK+ ICE+IL-2 combo. Targeted immunotherapy
(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
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).
FATE's targets BCMA, CD19,.HER2.. make it not investable. Too many ACTs, ADCs targeting the same.
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.
FT536 preclinical data https://www.cell.com/med/fulltext/S2666-6340(23)00136-8
Fate Therapeutics Leaders Misrepresented J&J Tie, Investor Says https://news.bloomberglaw.com/securities-law/fate-therapeutics-leaders-misrepresented-j-j-tie-investor-says
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.
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
(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/
(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.
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%.
If NKX101 is successful, it would establish proof-of-concept, and could enable them to evaluate a broader solid tumour clinical development program.
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.
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.
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
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