Periodic Reporting for period 1 - PolyAntiTumor (Polyclonal anti-tumor immunity by engineered human T cells)
Période du rapport: 2022-10-01 au 2025-03-31
Solid tumors remain a major challenge in cancer treatment, as most current T cell therapies are ineffective against them due to tumor resistance mechanisms, such as antigen loss and immune evasion. This project addresses these critical gaps by leveraging advanced CRISPR-Cas9 genome engineering to develop T cell therapies that are robust, precise, and capable of overcoming these obstacles. Our overarching goal is to engineer T cells with enhanced efficacy, safety, and specificity by focusing on three key aims: optimizing T cell receptor (TCR) sensitivity to improve therapeutic persistence, uncovering and controlling self-reactive T cells to minimize adverse effects, and creating polyclonal TCR repertoires that counteract tumor antigen loss. A key innovation is the development of a platform for scalable TCR knock-in, which eliminates the need for complex manipulation and expands the accessibility of these therapies. The expected impact of this work is transformative: it will provide new scientific insights into T cell biology and redefine engineered immunotherapies for cancer, ultimately making these treatments safer, more effective, and available to a broader range of patients.
Since the beginning of the project, we have made significant progress toward the three main aims. For Aim 1, we optimized TCR knock-in protocols, improving efficiency and T cell viability to enhance both effector function and persistence. Additionally, we demonstrated that repetitive stimulation reduces T cell killing capacity, highlighting the importance of fine-tuning TCR signaling. For Aim 2, we developed approaches to identify self-reactive T cells, including the use of RASA2 knockout to uncover activation markers and initial studies with thyroglobulin-reactive T cells in healthy donors. For Aim 3, we advanced a scalable TCR knock-in platform that eliminates reliance on ex vivo manipulation, offering a transformative approach to T cell engineering. These achievements lay a strong foundation for safer, more effective, and accessible engineered T cell therapies and mark a significant step toward overcoming the challenges of treating solid tumors.
We have made significant progress beyond the state of the art by optimizing TCR knock-in protocols to improve efficiency and viability, demonstrating that RASA2 knockout uncovers self-reactive T cells in healthy donors, and developing a scalable TCR knock-in platform. These advancements mark critical steps toward safer, more effective, and accessible engineered T cell therapies. By the end of the project, we expect to further refine these approaches, publish key findings, and advance the translational potential of our work.