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• W4308398265 abstract "<h3>Background</h3> Mutations in the <i>RAS</i> family of genes are responsible for approximately 30% of all human cancers. Mutated RAS proteins are truncal oncogenic driver antigens essential for cancer development and progression making them optimal targets for cancer therapies by limiting tumor escape. The AFNT-111 cell therapy consists of autologous CD8⁺ and CD4⁺ T cells expressing a TCR specific for the highly prevalent KRAS_G12V mutation presented by HLA-A*11:01, one of the most common HLA alleles worldwide. AFNT-111 is also engineered to express the CD8α/β coreceptor, enabling a coordinated CD4⁺/CD8⁺ tumor response that aims to promote increased T cell activity and persistence while minimizing T cell exhaustion. <h3>Methods</h3> Lentiviral vector was used to transduce primary human CD4⁺ and CD8⁺ T cells with the KRAS_G12V-specific TCR and CD8α/β coreceptor. Engineered T cells were assessed against KRAS_G12V peptide and a panel of KRAS_G12V-expressing tumor cell lines for <i>in vitro</i> activation, proliferation, and cytotoxicity. <i>In vitro</i> safety studies were performed to evaluate self-peptide cross-reactivity and alloreactivity and <i>in vivo</i> efficacy studies were conducted using human KRAS_G12V xenografts in NSG mice. <h3>Results</h3> AFNT-111 demonstrated potent functional avidity for KRAS_G12V peptide with no reactivity to wildtype KRAS. Several naturally expressing KRAS_G12V human tumor cell lines, derived from lung, colorectal, and pancreatic cancer, triggered significant AFNT-111 T cell activation and proliferation, and potent cytotoxicity towards tumor cells. <i>In vitro</i> killing by AFNT-111 was consistently observed even after repeated tumor cell challenge. Robust <i>in vivo</i> anti-tumor efficacy was also observed in two established mouse xenograft tumor models. XScan studies using amino acid substitutions of the reference KRAS_G12V peptide revealed a restrictive TCR recognition motif limiting risk of promiscuous off-target activation. Further, potentially cross-reactive self-peptides in the human proteome matching this motif were tested and no cross-reactivities with significant avidity were identified. A large lymphoblastoid cell line library covering >95% of the most common HLA alleles was assessed with no alloreactive responses detected. For clinical studies, a robust manufacturing process has been developed in which CD4⁺/CD8⁺ T cell ratios are controlled, and the final AFNT-111 drug product preserves stem-like properties. <h3>Conclusions</h3> AFNT-111 preclinical data demonstrate a highly potent and specific TCR-engineered T cell product that is cytotoxic to KRAS_G12V-expressing tumor cells both <i>in vitro</i> and <i>in vivo</i>. Cross-reactivity and alloreactivity assessments established a strong safety profile of AFNT-111, supporting clinical translation. First-in-human clinical studies will focus on advanced or metastatic pancreatic, colorectal, and lung cancer indications. <h3>Ethics Approval</h3> These studies were approved by Affini-T Therapeutics and Fred Hutchinson Cancer Research Center Ethics Boards, approval number EB17-010-303 and PROTO000050898, respectively." @default.
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• W4308398265 date "2022-11-01" @default.
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• W4308398265 title "244 AFNT-111, a safe and effective TCR-engineered T cell therapy targeting the oncogenic driver KRAS G12V mutation" @default.
• W4308398265 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0244" @default.
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