KRAS mutations are prevalent in various types of solid tumors and play a significant role in cancer development and progression. While approved small molecule inhibitors target KRAS G12C mutations, there is currently a lack of targeted therapies for patients with the highly prevalent KRAS G12V mutations. Clinical trials have shown promising responses with TCR-T cell therapies, but their effectiveness has been limited by the immunosuppressive nature of the tumor microenvironment (TME). AFNT-211 is an autologous T cell therapy that has been genetically engineered to express an HLA-A*11:01 KRAS G12V-specific TCR. Additionally, it is enhanced with the CD8α/β co-receptor and a FAS-41BB switch receptor, aiming to promote T cell persistence and achieve durable clinical responses. The CD8α/β co-receptor facilitates coordinated CD4+/CD8+ T cell response, while the FAS-41BB switch receptor converts the FAS ligand (FASL) TME death signal into a costimulatory signal through 41BB activation.
When AFNT-211 was cultured alongside various tumor cell lines expressing KRAS G12V, it resulted in notable secretion of effector cytokines, T cell proliferation, and effective killing of tumor cells. The presence of the CD8α/β co-receptor facilitated the recognition of KRAS G12V by CD4+ T cells, leading to enhanced overall cytotoxicity. The incorporation of the FAS-41BB switch receptor significantly amplified both the magnitude and durability of the anti-tumor response, particularly against tumor cells expressing FASL. Thorough testing, including XScan mutagenesis and off-target peptide analysis, demonstrated no significant cross-reactivities. Furthermore, there were no instances of alloreactivity observed against a panel of lymphoblastoid cell lines representing the most common HLA types in the US population. In an in vivo mouse xenograft model, AFNT-211 exhibited a potent anti-tumor response. The Thrive manufacturing platform employed by Affini-T consistently delivers a high quantity of TCR-engineered T cells, ranging from >30-40e9, with a substantial proportion of these cells exhibiting characteristics of naïve and central memory T cells, while expressing minimal markers associated with exhaustion.
KOL insights
“We are pleased to present novel preclinical data from our cell therapy targeting KRAS G12V, highlighting the robust stemness properties of our cell product as a key aspect of its comprehensive characterization. These findings establish a solid research foundation and support our ongoing effort to advance the program as a potential paradigm-shifting treatment for solid tumors” –Expert Opinion.
Conclusion: AFNT-211 is an innovative TCR-T cell therapy that aims to achieve long-lasting therapeutic responses. It incorporates a highly effective KRAS G12V TCRCD8a/B co-receptor and FAS-41BB switch receptor to enhance its pharmacological activity. The THRIVE T cell manufacturing process enables the production of large quantities of AFNT-211 drug product, which exhibits desirable characteristics such as naïve and central memory phenotypes. Extensive preclinical studies have demonstrated potent and specific pharmacological activity of AFNT-211 in both in vitro and in vivo settings, while maintaining a safe profile. With these promising results, AFNT-211 is poised for clinical translation, and the following trial design will facilitate its further evaluation
