Abstract B006: 2T2T: 2 week turnaround to personalised TCR therapy: Rapid identification, validation and prioritization of patient-specific, cancer-targeting TCRs

Abstract Personalized cell therapies engineer millions of a patient’s T cells to recognize and kill cancer cells using a patient derived cancer-targeting T cell receptor (TCR). The results can be impressive: in an early trial a patient with late stage metastatic breast cancer refractory to chemotherapy was completely cured of cancer 1. Unfortunately the process of identifying a suitable cancer-targeting TCR for a patient is labor intensive, slow and thus expensive, taking 3-6 months in a commercial setting 2. While pipelines utilizing cancer genome sequencing identify high quality, neoepitope-specific TCRs, the long turnaround time is too slow to be of clinical utility for many patients, and too expensive for widescale use. We used >100,000 TCRs to train the ‘predicTCR’ machine learning classifier to identify tumor-reactive TCR clonotypes form single-cell sequenced tumor infiltrating lymphocytes (TILs) samples. predicTCR is over 85% accurate at detecting tumor-reactive TCRs across diverse tumor types and sequencing technologies 3. predicTCR is antigen agnostic, recognizing tumor-reactive T cells clonotypes in minutes. We then developed makeTCR: a rapid, modular TCR cloning platform to manufacture candidate tumor-reactive TCRs in as little as 24 hours 4. Using makeTCR, candidate TCRs’ tumor killing capacity is validated and TCRs prioritized using autologous T cells and either patient cancer cells or individualized patient-derived tumor organoids (IPTOs) 5. We have combined these platforms to generate the 2T2T pipeline, enabling a 2 week turnaround to patient-specific TCR therapy using experimentally validated TCRs. Our tools are available to the scientific community at https://predictcr.com and https://maketcr.com. 1. Zacharakis et al (Nature Medicine 2018). Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer 2. Foy et al (Nature 2023). Non-viral precision T cell receptor replacement for personalized cell therapy. 3. Tan et al (Nature Biotechnology 2024). Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy. 4. Hamberger et al (biorxiv 2025). makeTCR: A Modular Platform for Rapid, Flexible, Scalable, Single-Step T Cell Receptor Synthesis. 5. Peng et al (Cell Stem Cell 2025). Individualized patient tumor organoids faithfully preserve human brain tumor ecosystems and predict patient response to therapy. Citation Format: Chin Leng Tan, Tamara Boschert, Marie-Therese Neuhoff, Moritz Hamberger, Amelie C. Dietsch, Katherina Lindner, Claudia Maldonado-Torres, Alina Errerd, Isabel Poschke, John M. Lindner, Hai-Kun Liu, Lukas Bunse, Michael Platten, Edward W. Green. 2T2T: 2 week turnaround to personalised TCR therapy: Rapid identification, validation and prioritization of patient-specific, cancer-targeting TCRs [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B006.