Enhancing Solid Tumor Therapy with OPB-101: A Mesothelin-Targeted CAR T Cell Approach

Solid tumors have posed a challenge for T cell therapies due to their inability to effectively proliferate post-infusion. To address this, a novel mesothelin (MSLN) CAR T product, OPB-101, has been developed. This product incorporates a unique promoter, OP1, an enhanced chimeric antigen receptor (CAR), a safety mechanism, and a specialized cytokine, CD8α-targeted IL-2/15, to stimulate T cell growth and improve treatment efficacy.

The human anti-MSLN binders were refined using the OUTSPACERTM library for precise targeting. The CAR's effectiveness was evaluated in vitro and in vivo using NSG tumor xenograft models. The OUTSMARTTM IL-2/15 cytokine was crafted to prevent activation of regulatory T cells by eliminating IL-2Rα binding and focusing on CD8α to boost CD8+ T cell and NK cell activity. Additionally, EGFRoptTM was designed to increase sensitivity to EGFR-targeted therapies.

The OP1 promoter was utilized to control the expression of the CAR, cytokine production, and exhaustion resistance in an antigen-dependent manner. The OPB-101 construct was tested for its ability to counteract T cell exhaustion and its in vivo effectiveness was measured in mice with H1650 tumors that received varying doses of OPB-101 T cells via intravenous injection.

OPB-101 demonstrated potent MSLN+ tumor cell line elimination capabilities and controlled IL-2/15 cytokine production. The cytokine's expression did not lead to uncontrolled CAR T cell proliferation but supported survival in the absence of external cytokine support. In in vivo studies, OPB-101 showed complete and sustained tumor eradication even at the lowest tested dose, a significant contrast to the modest effects observed with the CAR-only condition.

The anti-tumor efficacy of OPB-101 correlated with robust T cell expansion in the peripheral blood and intratumorally, along with reduced levels of exhaustion markers such as PD-1, TIGIT, and CD39. Notably, the in vivo expansion of OPB-101 was contingent on the presence of the tumor.

In conclusion, the OPB-101 product leverages a regulated promoter and an optimized MSLN CAR, along with EGFRoptTM and a CD8-targeted IL-2/15 cytokine, to enhance its anti-tumor effectiveness against solid tumors. This approach supports the complete elimination of solid tumors at a low treatment dose, offering a promising advancement in CAR T cell therapy for solid tumors.