Difference between revisions of "Team:Fudan/Applied Design"

Antigen density on tumor cells’ surface is heterogeneous. Current cellular immunotherapy only targets cells with high expression of specific tumor antigen. While this approach can improve the precision of recognition, it loses the opportunity to strategically treat tumor cells with different surface antigen densities. We are the first to propose a cellular immunotherapy platform, SwordS (SynNotch-Stripe system), that is capable of generating non-monotonic therapeutic responses to one tumor antigen with different surface densities. We demonstrated our concept with the following experiments. In combining a SynNotch module, which can recognize the antigen, and a Stripe module, which can sort intracellular signal, our engineered cells could generate antigen density dependent tri-response against the target cells with different densities of surface GFP, as well as membrane GPC3 (the tumor antigen of hepatocellular carcinoma). Both experimental data and mathematical simulation show that our platform not only reduces the on-target/off-tumor effects of the original SynNotch system, but also provides a combinational therapeutic solution to treat tumor at various states. We believe that SwordS is a promising platform for the next generation cellular immunotherapy.

The expression of the antigen on individual cells within a given tumor is different or heterogeneous. A solid tumor mass consists of numerous tumor cells. In these tumor cells, some may express relatively less tumor antigens, others may express relatively more tumor antigens. Meanwhile, a given tumor antigen is not only expressed on malignant cells, but may also be expressed on normal cells at a low level (Figure 1A). Thus, normal cells expressing low level of tumor antigens subsequently should not be targeted, otherwise would casuse complications. Carefully control the on-target/off-tumor effect is critical for the success of immunotherapy. (Figure 1B)

Carcinogenesis is a gradual progress driven by the accumulation of mutations. Tumor cells are highly heterogeneous in their surface tumor antigen expression⁽¹⁾, thus immune resistance⁽²⁾, sensitivity to the treatment and so on. Meanwhile, efficient recognition by immunotherapy, as one of the fundamental challenges for solid tumors, is still in the way comparing with exciting results shown in treating hematological cancers⁽³⁾.Currently, most existing immunotherapies exhaust in trying multiple methods to improve recognition^(4-6), without considerating tumor heterogeneity. They focus narrowly on finding an ideal tumor antigen as the target and hope to generate a effective therapeutic response – monotonic response.We believe these conventional one-size-fits-all immunotherapies cannot adapt itself to all complex disease occasions in various types of tumors.(Figure 1B)

Tumor in different states need different treatments. To develop rational combined therapy, the key question is how to accurately manifest tumors’ condition. Fortunately, with improved understanding of oncogenesis and emerging therapies, clinical trials of rational combined therapy have become possible^(14,15). Through investigation, we found that antigen density heterogeneity, tumor antigen level and expression pattern are associated with disease progression(16).Thus, Antigen density heterogeneity could be used to develop rational combined immunotherapy.

Here, we report the “SwordS”, SynNotch-Stripe system, which can spontaneously generate non-monotonic responses by targetingdifferent surface tumor antigen density of tumor cells at different states.(Figure 2)