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.