Improving tumor specificity of cellular immunotherapies

Cancer therapy using immune cells is one of the most promising new approaches in cancer treatment. One specific method involves CAR-T cells. These are immune cells (T-lymphocytes) that are genetically modified to recognize and destroy cancer cells. CAR-T cell therapy has proven highly effective in treating B-cell leukemias and lymphomas. However, its effectiveness against other types of tumors is still very limited. One of the main challenges is that CAR-T cells in nearly all cases attack not only cancer cells but also healthy tissues. This makes it difficult to develop more potent CAR-T cell therapies without causing harmful side effects. Thus, before we can safely improve the potency of these cells, we need to develop methods that prevent them from attacking healthy tissue. In our lab, we have developed a specialized CAR platform, called "AvidCARs," to improve tumor specificity. This platform leverages the principle of amplified activation of T cells by increasing binding strength through the simultaneous recognition of two distinct target antigens on cancer cells. T- lymphocytes equipped with AvidCARs only eliminate cells that display both antigens, sparing those that express just one. This dual-antigen recognition is key to ensuring that only cancer cells are targeted, reducing the risk of attacking healthy tissue. However, it is not only crucial to improve the specificity of CAR-T cells, but also their sensitivity so that they can detect and attack cancer cells even when only low levels of both target antigens are present. This is the aim of the present project. In this project, we build on our strategy of amplifying the strength of individual bindings through dual antigen recognition and will enhance the sensitivity of tumor cell recognition by improving the transduction of the activation signal in the T-lymphocytes. Although several approaches have already been developed to improve the tumor specificity of cellular immunotherapies, there is still a huge need for tools that offer enhanced functionality and improved clinical applicability. These novel tools are essential to unlocking the full potential of this immunotherapy and enable effective treatment of a broad range of cancers.

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