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Abstract
Background Although effective in multiple liquid tumor indications, chimeric antigen receptor (CAR)-T cells have limited efficacy in solid tumor settings. This is the result, in part, of the challenge differentiating tumor associated antigen (TAA) expression in normal and tumor tissue, heterogeneity of TAA expression in the tumor itself, and the lack of effective strategies to simultaneously enhance effector cell trafficking to, persistence within, and resistance to the suppression found within the tumor microenvironment (TME). Here we describe FT825/ONO-8250, a seven-point edited, off-the-shelf CAR-T cell therapy specifically engineered to address and overcome barriers for effective cell therapy in solid tumors.
Methods Induced pluripotent stem cells (iPSCs) were engineered to express a novel CAR targeting HER2, interleukin-7 receptor fusion protein (IL7RF), TGFβ-signal redirection receptor (TGFβ-SRR), high-affinity non-cleavable CD16A (hnCD16), and CXCR2 alongside CD38 and T cell receptor, alpha deletion. Engineered iPSCs were differentiated into alpha-beta T (iT) cells, uniformly expressing engineered transgenes without CD38 or T-cell receptor expression, limiting the risk of graft-versus-host disease from allogeneic therapies.
Results FT825/ONO-8250 demonstrated potent and specific CAR-based targeting of tumor target lines across HER2 expression levels (3+ to 1+) from multiple solid tumor indications (figure 1A). CAR-dependent efficacy was further enhanced when combined with therapeutic antibodies to trigger antibody-dependent cellular cytotoxicity (ADCC) via hnCD16. Unlike Herceptin-based primary CAR-T cells, FT825/ONO-8250 demonstrated limited cytotoxicity on multiple normal, non-tumorigenic cell lines, underscoring the preference of FT825/ONO-8250 for HER2 expressed by tumor cells (figure 1B). FT825/ONO-8250 resisted TGFβ-mediated suppression, maintaining robust cytolytic efficacy across multiple rounds of tumor challenge and TGFβ exposure, the result of TGFβ-SRR expression. IL7RF enhanced the persistence of FT825/ONO-8250, and CXCR2 expression enabled specific and potent migration to CXCR2 ligands enriched within diverse solid tumor indications. Finally, we observe robust anti-tumor efficacy in vivo in subcutaneous HER2+ xenograft models (figure 1C).
Conclusions FT825/ONO-8250, engineered to (i) preferentially target tumor-expressed HER2 and (ii) overcome solid tumor heterogeneity, resist tumor microenvironment suppression, and enhance solid tumor trafficking, is scheduled for IND submission in 2H 2023.
Ethics Approval These studies were approved by Fate Therapeutics Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.
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