Polyclonal anti-tumor immunity by engineered human T cells

Project Information

PolyAntiTumor

Grant agreement ID: 101042941

DOI

10.3030/101042941

EC signature date 17 February 2022

Start date 1 October 2022

End date 30 September 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 812 500,00

EU contribution

€ 1 812 500,00

Coordinated by

TEL AVIV UNIVERSITY
Israel

Periodic Reporting for period 1 - PolyAntiTumor (Polyclonal anti-tumor immunity by engineered human T cells)

Reporting period: 2022-10-01 to 2025-03-31

Summary of the context and overall objectives of the project

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.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

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.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

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.