Century Therapeutics Inc (IPSC) Quote

Links https://www.centurytx.com/wp-content/uploads/ASGCT-2025-TGF-B-Neutralizing-Synthetic-Receptor.pdf

https://www.centurytx.com/wp-content/uploads/ASGCT-2025-iPSC-derived-abT-cells.pdf

1) Armoring iPSC-derived allogeneic therapies with a TGF-b neutralizing synthetic receptor that enhances solid tumor elimination in TME-mimicking conditions in vitro

Allogeneic immunotherapy holds immense promise for solid tumor treatment with significant challenges remaining in overcoming the barriers imposed by the solid tumor microenvironment (TME). Extensive preclinical research has led to the pharmacological targeting of the Transforming Growth Factor Beta (TGF-ß) pathway, which plays a key role regulating TME. TGF-ß drives immunosuppression, stromal remodeling, and angiogenesis to support tumor progression. Here we describe solid-tumor-targeted induced pluripotent stem cells (CAR-iPSC) armored with a synthetic dominant negative receptor (DNR) that neutralizes TGF-ß in the environment, thereby potentially inhibiting tumor growth and enhancing immune responses against cancer. We established compatibility of TGF-ß DNR engineering with iPSC differentiation and successfully generated TGF-ß DNR CAR-iT cells. We confirmed that TGF-ß DNR-engineered CAR-iPSCs have reduced SMAD signaling in the presence of soluble TGF-ß compared to non-engineered CAR-iPSC by flow cytometry.

We evaluated CAR-iT (+/- TGF-ß DNR) function in the presence of inhibitory TGF- ß (5ng/mL) signals in a repeat-killing assay across multiple Nectin-4 positive target cells. We observed significant advantages of TGF-ß DNR CAR-iT in maintaining prolonged cytotoxic activity against labeled target cells by Incucyte in the presence of TME-mimicking conditions. Killing capacity was observed to be 4 times higher with expression of the TGF-ß DNR (1.05x10e10 for CAR-iT and 2.5x10e9 CAR-iT with TGF-ß DNR). Moreover, we observed a similar effect in a spheroid tumor model, indicating the ability of TGF-ß DNR to sustain cytotoxic activity in a 3D culture system. Additionally, we’ve observed improved function in armored Peripheral blood mononuclear cell-derived iPSC-derived CAR-iNK with TGF-ß DNR. In summary, we can improve cytotoxic activity of targeted CAR-iT and CAR-iNK engineered with TGF-ß DNR against solid tumor cell lines in the presence of recombinant human TGF-ß. These findings highlight a modality that can confer improved anti-tumor activity of future iPSC-derived immunotherapies designed to withstand the immunosuppressive nature of the TME.

2) Generation of iPSC-derived CD4+ and CD8+ CD19 CAR aß T cells with in vivo tumor control and cell expansion comparable to healthy donor T cells

Successful development of off-the-shelf CAR-T cell therapies requires complex engineering to i) prevent graft vs host disease (GvHD) and rejection by the patient’s immune system, and ii) equip the cells with anti-tumor capabilities, such as a chimeric antigen receptor (CAR). Induced pluripotent stem cells (iPSCs) provide an ideal platform; engineered clones can be characterized and banked for future differentiation due to the unique ability of these cells to both self-renew and retain the potential to make any cell in the adult body. Using a scalable feeder-free method, we report the generation of allogeneic iPSC-derived CAR T cells with comparable function to primary T cells. iPSCs were engineered with a CD19 CAR and allo-evasion edits designed to combat cellular and humoral responses. A fully characterized clone was selected and differentiated using a novel process that generated a mix of CD4+ and CD8+ T cells. scRNA-seq analysis of cells at different stages of this process confirmed that cells follow a trajectory matching normal thymocyte development to aß T cells.

Upon in vitro tumor challenge, these iPSC CAR T cells displayed Ag-dependent cytotoxicity, proliferation, and cytokine production, including IL-2. A single infusion of Century iPSC-CAR-T cells demonstrated tumor control in an established NALM6 tumor model without the need for exogenous cytokines or cytokine engineering. Importantly, iPSC-CAR-T cells persisted in peripheral blood for at least 21 days, trafficked to the bone marrow, and measurably proliferated upon tumor rechallenge in an in vivo model. Both in vivo proliferation and tumor control were at least comparable to primary T cell controls. These data are a significant advance in the field of allogeneic iPSC CAR T cells and support the use of this platform for the development of scalable, accessible CAR T cell medicines.

Link https://edge.media-server.com/mmc/p/kyvcrvor/

Fireside Chat https://www.globenewswire.com/news-release/2025/04/15/3062105/0/en/Century-Therapeutics-to-Host-Live-Fireside-Chat-Focused-on-Newly-Prioritized-Preclinical-Cell-Therapy-Programs-for-Autoimmune-Diseases-and-Cancer-on-Tuesday-April-22-2025.html

Upcoming at Upcoming at ASGCT

Armoring iPSC-derived allogeneic therapies with a TGF-b neutralizing synthetic receptor that enhances solid tumor elimination in TME-mimicking conditions in vitro.

Generation of iPSC-derived CD4+ and CD8+ CD19 CAR ab T cells with in vivo tumor control and cell expansion comparable to healthy donor T cells.

Upcoming (in June)

Generation of iPSC-Derived CAR-NK, gd CAR-T, and ab CAR-T Cells with Potent Activity for Treatment of B cell-mediated Autoimmune Diseases https://apps-congress.eular.org/eular25/en-GB/pag/presentation/20833

CNTY-101, an iPSC-Derived Allogeneic CD19 Targeting CAR-NK Product, Exhibits Robust B Cell Depletion and Has Broad Potential for Development in B Cell-Driven Autoimmune Diseases https://apps-congress.eular.org/eular25/en-GB/pag/presentation/20828

It is too risky for IPSC, so I will watch from the sidelines. As for FATE, I will wait to see the data (FT819) that should be presented at the EULAR Congress, in June.

Tim walbert on Boards is a red flag bleed the stock dry similar situation will happen with SGMT hes on that board you have a CRSP founder as the CEO of century therapeutics stay away from gene editing stocks most fail.

$IPSC

LOL - jondoeuk & theoryslut!!! KARMIC Reflection....👀👀👀

do you have an lean between IPSC or FATE? Both look worth a lotto shot at discount to cash levels.

ipsc..............................https://stockcharts.com/h-sc/ui?s=ipsc&p=W&b=5&g=0&id=p86431144783

IPSC, under $2

IPSC......................https://stockcharts.com/h-sc/ui?s=IPSC&p=W&b=5&g=0&id=p86431144783

ASH abstracts

Successful Generation of iPSC-Derived CD4+ and CD8+ CAR T Cells with aß-like T Cell Function, Including Antigen-Dependent Expansion and IL-2 Production https://ash.confex.com/ash/2024/webprogram/Paper210428.html

Universal Cloaking of Allogeneic T Cell Therapies Against Natural Killer Cells Via CD300a Agonism https://ash.confex.com/ash/2024/webprogram/Paper211844.html

Optimizing Chimeric Antigen Receptor Endodomains for Effector Function and Cell Expansion in iPSC-Derived T-Cell Therapies https://ash.confex.com/ash/2024/webprogram/Paper210516.html

Leveraging Stage-Specific Promoters to Enhance Immune Cell Engineering in iPSC-Derived Cells for Cancer Immunotherapy https://ash.confex.com/ash/2024/webprogram/Paper210942.html

Natural Killer and ?d T Cells Derived from Engineered Induced Pluripotent Stem Cells Have Potent Preclinical Activity to Treat B Cell-Mediated Autoimmune Diseases https://ash.confex.com/ash/2024/webprogram/Paper210234.html

WOUND TIGHT

IPSC HERE WE GO

ISPC RIGHT SYMBOL POST SPLIT

OT: First allo CAR-NK (data) https://acrabstracts.org/abstract/allogenic-cd19-car-nk-cells-therapy-in-refractory-systemic-lupus-erythematosus-an-open-label-single-arm-prospective-and-interventional-clinical-trial/

IPSC under $2

The new CSO founded Clade and served as its CEO. Dr. Cowan was a scientific founder of CRSP and founder and CSO of SANA as well https://finance.yahoo.com/news/century-therapeutics-strengthens-leadership-team-110000642.html

IPSC under $3

Something else Gadeta had been working on https://aacrjournals.org/cancerres/article/84/6_Supplement/3611/737213/Abstract-3611-A-patient-derived-organoid-platform

The single doses were nothing to write home about, and only one patient enrolled so far for the multiple doses https://www.globenewswire.com/news-release/2024/06/03/2892097/0/en/Century-Therapeutics-Presents-Interim-Results-from-Phase-1-ELiPSE-1-Study-at-ASCO-2024-Annual-Meeting.html

Poster https://www.centurytx.com/wp-content/uploads/20240517_Century_ASCO_FINAL.pdf

ASGCT PR https://finance.yahoo.com/news/century-therapeutics-presents-preclinical-data-110000872.html

The other poster

The poster

Preprint https://www.biorxiv.org/content/10.1101/2024.05.05.592600v1

Last year Clade Therapeutics announced the acquisition of Gadeta B.V. https://www.globenewswire.com/news-release/2023/10/02/2752753/0/en/Clade-Therapeutics-Announces-the-Acquisition-of-Gadeta-B-V.html

Gadeta was developing cell therapies expressing defined gamma-delta T-cell receptors that specifically recognise cancer cells. In order to harness the unique targeting properties of gamma-delta TCRs, Gadeta developed the TEG platform, which equips alpha-beta T-cells (used in the production of CAR and TCR therapies) with a defined gamma-delta TCR https://www.sciencedirect.com/science/article/pii/S0006497120448153

Gadeta also developed a novel proprietary gamma-delta TCR discovery engine based on a 'TCR centric' selection approach that sourced patient material (for a broad range of naturally selected gamma-delta TCRs from different tissues), screened (to identify tumour reactive gamma-delta TCRs from co-cultures of patient material) and selected gamma-delta TCRs optimal properties. Some preclinical data https://aacrjournals.org/cancerres/article/82/12_Supplement/2818/701504/Abstract-2818-Targeting-solid-tumors-with-GDT002-a

Upcoming (Fri, May 10) https://annualmeeting.asgct.org/program/agenda-speaker-details?agendaId=37279



As for the antibody degrader, I don't see them being able to combine the cells with therapeutic antibodies. But they might not need to add it.

Acquisition of Clade Therapeutics https://www.globenewswire.com/news-release/2024/04/11/2861378/0/en/Century-Therapeutics-Strengthens-Position-in-Autoimmune-Disease-with-Strategic-Pipeline-Expansion-Supported-by-60-Million-Private-Placement-and-Acquisition-of-Clade-Therapeutics.html

Some slides

IPSC under $5

In 1.60
Out 4.35

Doesn't look that way with auto CAR-T. Out of the 15 treated, all had auto-antibodies, with 13 in skin, 11 in lung, 9 in kidney, 9 in joints, 4 in the heart, 3 in muscle, and other organs. Renal (kidney) disease occurs in up to 40% of patients and can evolve to kidney failure requiring dialysis and is associated with higher risk of death.

CSO was smart selling off his shares. Depleting B cells is not investable, trading in SLE for B cell aplasia is a good deal?

Additional data https://century-therapeutics-initial-clinical-data-call.open-exchange.net/registration

Slides https://investors.centurytx.com/static-files/b88aac71-fffe-4b39-9573-82e3964f79b1

The PR https://www.biospace.com/article/releases/century-therapeutics-presents-initial-data-from-cnty-101-phase-1-elipse-1-trial-supporting-the-potential-for-a-multi-dosing-strategy-for-car-ink-enabled-by-allo-evasion-edits/

Poster https://www.centurytx.com/wp-content/uploads/2023-ASH-poster_Century-Tx_FINAL.pdf

Summary of the case that is going to be presented at ASH https://ash.confex.com/ash/2023/webprogram/Paper182313.html

Patient with high-risk R/R follicular lymphoma. Completed four 28-day cycles of CNTY-101 at the 100 million cell dose (DL1), first two administered following lymphodepletion, while the most recent two were administered without lymphodepletion. All doses of CNTY-101 with and without IL-2 or LD were well tolerated and demonstrated clinical benefit as defined as stable disease or better (per Lugano 2014 criteria). Responses were associated with tumour shrinkage and an ongoing CR of a duration of five months since the first CNTY-101 infusion. The PK data showed that CNTY-101 cells were detected after each infusion with comparable kinetics, with a limited duration in circulation. No measurable CDC-inducing functional ADA detected in any samples by data cut-off (including the first three cycles). Treatment was associated with changes in tumour microenvironment within eight days post-infusion, augmentation of adaptive T-cell responses, and tumour shrinkage.

CSO sold off his shares not sure why

Extensive epigenetic and transcriptomic donor-specific differences observed in iPSC derived allogenic NK (iNK) cells https://www.abstractsonline.com/pp8/#!/10828/presentation/6083

iPSC-derived CAR-NK cell therapy: nominating clinical candidate clones through integrated multi-functional analysis https://www.abstractsonline.com/pp8/#!/10828/presentation/3328

Link to the webcast https://century-therapeutics-virtual-research-development-day.open-exchange.net/registration

The company will host a virtual Research and Development Day on Friday, Nov 11, from 8:00 AM to 9:30 AM ET. The R&D Day will feature presentations from the management team and Jonathan Rosenberg, M.D., Chief of the Genitourinary Oncology Service at the Memorial Sloan Kettering Cancer Center, Physician at Memorial Hospital, and Professor of Medicine at Weill Cornell Medical College. The event will focus on the company's solid tumour strategy and gamma delta iT cell platform, including a discussion on preclinical data to be presented at the Society for Immunotherapy of Cancer Annual Meeting.

SITC titles

Empowering iPSC-Derived iNK Cells with Multiple Gene Edits to Improve Persistence and Anti-Tumor Efficacy

Multiple Targeting of Solid Tumors with iPSC-derived Gamma Delta CAR T Cells in Combination with Therapeutic Antibodies

Yes, and the expansion cohorts will include both CAR-T naïve and relapsed. Next data from them should be around Dec, so ASH or an investor event. They have decided not to go past 1.5B cells per dose (x three doses) for some reason. Based on the data so far there is a dose response relationship (300M or 1B per dose) and all CRs are ongoing.

They should. High-affinity CD16 variants in the population correlate with clinical outcomes, so better objective responses and progression-free survival. However, the CD16 receptor is cleaved from the surface of activated NK cells, which leads to dysfunction and reduced antibody-dependent cellular cytotoxicity.

FATE could present some early clinical data on both at FT538 and FT536 at SITC. The former is being tested in combo with mAbs, while the latter (has an added CAR, along with the same three edits* as the other) is as a single agent or with mAbs.

* https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00350-7

NKTX seems to repeat what DTIL tried with 19a/eLD. Why they don't increase the NK cells dose to 4 billions same as AUTO NK?

Will the ISPC NK cells work if the mAb is the weakest link? .AFM24 v. cetuximab hold the key to success?

AZ just stopped the trial of monalizumab in combination with cetuximab vs. cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

Looking at P1 data from Fate and NKTX, NK cells seem to be effective on indolent lymphoma and nodal DLBCL.

FATE and NKTX have other trials ongoing in certain haematological malignancy. Adoptive transfer can induce long-term and durable remissions after a haploidentical stem cell transplantation in R/R AML. In those that are unable to undergo transplantation across seven published studies (over one hundred patients in total), 34% achieved a complete response to NK cell therapy alone. However, it has been demonstrated that the absence of NKGD2 ligand expression on leukemic stem cells determines therapy resistance and immune escape. PARP1 inhibitors can induce expression of NKG2D ligands, so I would like to see certain combo therapies https://www.nature.com/articles/s41586-019-1410-1

For pts with high tumor burden or aggressive disease, CART will still be needed.

Even for CAR-T, intensive debulking chemo could help those with a high tumour burden https://www.frontiersin.org/articles/10.3389/fonc.2021.706087/full

I listened to NKTX presentation, the number of cycles given to a patient will be up to the oncologist.

In June, NKTX filed a protocol amendment with the FDA for the ongoing PhI trial of NKX019 to optimise the trial's design as the company prepares for potential dose expansion cohorts. The amended protocol, now in effect, allows for an increased dose of cyclophosphamide, in line with NKX101, and various expansion cohorts evaluating NKX019 in combination with rituximab. Also, three doses of CAR-NKs per cycle, with them currently enrolling a cohort testing 1.5 billion cells per dose.

According to a medical doctor on twitter they haven't been able to secure a source for the cbNKs. A second Fc receptor, CD64, binds to the same IgG's as CD16a, but with more than a 30-fold higher affinity. However, it is typically only expressed on myeloid cells, not NKs. FATE created a recombinant receptor consisting of the extracellular region of CD64 with transmembrane and intracellular regions of CD16a. Not only did they show activity, but additionally, the higher affinity of allowed for mAbs to be pre-adsorbed and improved targeting without additional mAb use. Also, they could still mix and match mAbs as well https://ashpublications.org/blood/article/136/Supplement%201/10/470430/Engineered-iPSC-Derived-NK-Cells-Expressing

AFMD seemed to have solved the cleaved CD16 issue by pretreating the NK with their AFM13 ex-vivo.

Looking at P1 data from Fate and NKTX, NK cells seem to be effective on indolent lymphoma and nodal DLBCL. For pts with high tumor burden or aggressive disease, CART will still be needed. I listened to NKTX presentation, the number of cycles given to a patient will be up to the oncologist.

Dr. Kaufman has presented some preclinical data

As for clinical, that comes from FATE and NKTX (using healthy donor), even though there are some differences between the programs in the same indications. From memory, in R/R NHL, FATE's best efficacy was achieved at a (much) lower dose (+/- rituximab), while NKTX had to go up to a billion across three doses (no rituximab).