Century Therapeutics Inc (IPSC) Quote

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).

Has anyone compared ISPC NK to CBNK?

Slides https://investors.centurytx.com/static-files/f0d80de2-1e62-49b5-acfd-0e1388c58179

Link to webcast https://kvgo.com/corporate-services/century-therapeutics-rd-event

The poster https://www.centurytx.com/wp-content/uploads/2022/05/ASGCT22_Enabling-the-Engineering-of-iPSC-Based-Cell-Therapies-Using-MAD7-a-Novel-CRISPR-Nuclease.pdf

A virtual R&D update will be held on June 13, at 4:30 PM ET. Century's management will discuss CNTY-103 and progress on the next-generation platform. Dr Sheila Singh, Professor of Surgery and Biochemistry, Chief Paediatric Neurosurgeon at McMaster Children’s Hospital, the Division Head of Neurosurgery at Hamilton Health Sciences, and the inaugural Director of McMaster's new Cancer Research Centre will discuss the current treatment paradigm in GBM.

952: Enabling the Engineering of iPSC Based Cell Therapies Using MAD7, a Novel CRISPR Nuclease https://annualmeeting.asgct.org/abstracts/abstract-details?abstractId=1867

ASGCT title:

Enabling the Engineering of iPSC Based Cell Therapies Using MAD7, a Novel CRISPR Nuclease.

Preclinical data on mbIL-15 https://ashpublications.org/blood/article/124/7/1081/33687/Autonomous-growth-and-increased-cytotoxicity-of

NKG2A https://www.jci.org/articles/view/123955

PET https://jnm.snmjournals.org/content/61/9/1348.long

As for allo evasion, it could be CD47 https://rupress.org/jem/article/218/3/e20200839/211668/The-SIRP-CD47-immune-checkpoint-in-NK-cellsSIRP

Data Disclosures

MAD7 nuclease in iPSC gene editing platform (2Q).
Epigenetics and cell reprogramming (2H).
CNTY-102 (4Q).
iNK platform 2.0 (4Q).

Events

R&D Day (GBM, CNTY-103 and Universal CAR) (1H).
R&D Day (TBD) (4Q).

Posters https://www.centurytx.com/wp-content/uploads/2022/01/Induced-pluripotent-stem-cell-derived-?d-CAR-T-cells-for-cancer-immunotherapy.pdf https://www.centurytx.com/wp-content/uploads/2022/01/Development-of-Multi-Engineered-iPSC-Derived-CAR-NK-Cells-for-the-Treatment-of-B-Cell-Malignancies.pdf

PR https://www.globenewswire.com/news-release/2021/12/16/2353430/0/en/Century-Therapeutics-Announces-Presentation-of-Data-at-the-63rd-American-Society-of-Hematology-Annual-Meeting-and-Provides-Pipeline-Updates.html

Slides https://investors.centurytx.com/static-files/517375cf-023b-4926-bd42-a0e3e7e8708e

R&D Update (Dec 16, from 8:00 AM to 9:30 AM EST)

Link to webcast https://kvgo.com/corporate-services/century-therapeutics-r-d-2021

ASH abstracts

Development of Multi-Engineered iPSC-Derived CAR-NK Cells for the Treatment of B-Cell Malignancies https://ash.confex.com/ash/2021/webprogram/Paper148438.html

Induced Pluripotent Stem Cell-Derived Gamma Delta CAR-T Cells for Cancer Immunotherapy https://ash.confex.com/ash/2021/webprogram/Paper149095.html

They are also working on an iT (BCMA + undisclosed) for myeloma, iNK or iT (multi-specific) for bladder, iNK or iT (multi-specific) for ovarian, iNK or iT (multi-specific) for RCC, and iNK or iT (multi-specific) for HCC.