Harnessing the Power of Stem-like TCR-T Cells: AFNT-211 in Targeting KRAS G12V Solid Tumors

3 June 2024
The text discusses a novel therapeutic approach for treating solid tumors driven by the KRAS oncogene. The KRAS G12V mutation, which is prevalent but lacks targeted treatments, is addressed by a T cell therapy called AFNT-211. This therapy utilizes engineered T cells that express a specific T cell receptor (TCR) for the KRAS G12V mutation. The engineered cells are equipped with a CD8α/β coreceptor to facilitate a coordinated immune response and a FAS-41BB switch receptor that converts a death signal from the tumor into a costimulatory signal, thereby enhancing T cell persistence and response.

The efficacy of AFNT-211 was evaluated both in vitro against various KRAS G12V-expressing cancer cell lines and in vivo using mouse models with human tumor grafts. Safety studies were conducted to examine potential cross-reactivity and alloreactivity, and the manufacturing process involves expanding autologous T cells using a lentiviral transduction method that maintains stem-like qualities.

Results showed that AFNT-211 induced substantial cytokine release, T cell expansion, and tumor cell death when cocultured with tumor cell lines. The incorporation of the CD8α/β coreceptor allowed for CD4+ T cell recognition of the KRAS G12V mutation, enhancing cytotoxicity. The FAS-41BB receptor significantly increased the strength and duration of the anti-tumor response, particularly against tumor cells expressing FASL. No significant cross-reactivities or alloreactivities were detected. In vivo studies in mice demonstrated a strong anti-tumor effect.

The manufacturing platform for AFNT-211 is capable of producing a large quantity of TCR-engineered T cells with high naive and central memory T cell frequencies and minimal exhaustion markers. The preclinical findings indicate that AFNT-211 has a potent and safe profile, making it a promising candidate for clinical trials in patients with advanced or metastatic solid tumors who possess the HLA-A*11:01 allele and a KRAS G12V mutation.

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