Century Therapeutics Inc【IPSC】株式ニュース

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.