Team:Fudan-CHINA/Background

Background
"What we do for ourselves dies with us. What we do for others and the world remains and is immortal."



As the primary cause of death, cancer has contributed to 1/6 of the total death number all around the world. According to the report of WHO in 2017, every passing minute means that another 17 names has been added to the victim of cancer. That's why it's become more and more urgent to find a method efficient enough for cancer treatment.
Compared to other means such as radiotherapy and chemotherapy, cell therapy has emerged with better results, higher speed of development as well as much more potential.

The current cell therapies mostly take advantage of existing or synthetic cell-surface biosensors to target and kill tumour cells. These biosensors include chimeric antigen receptor (CAR), synthetic Notch (SynNotch) and T-cell receptor (TCR). Up till now, the most successful case of cancer cell therapy is CAR-T, which uses engineered CARs – whose ectodomains are single-chain variable fragments (scFv) from monoclonal antibodies - to target certain cell-surface antigens on tumour cells1. These kinds of ectodomains can also enable TCRs to recognise specific tumour markers, and activate the intracellular signal pathways naturally existing in T-cells.

The two kinds of transducers take advantage of natural cellular pathways, but are also restricted by it, as the downstream could not be engineered and variant cellular reactions is hard to achieve2. SynNotch, which was firstly applied in tumour treatment in 2016, utilizes the same principles, the only difference being that the signal pathway was replaced by a cleaved transcription factor which is released into the cytoplasm and activate gene expression in nucleus upon recognisation3. By changing the transcription factor to non-human ones, the SynNotch system first realized orthogonality of biosensors used in cancer cell therapy.
However, receptors like CAR and SynNotch can only recognise antigens on cell surface. According to data of tumour markers published by National Cancer Institute (NIH), the 35 mostly used tumour markers in clinical practises include 21 which are mainly inside the blood. Because of the fact that the cell therapy biosensors mentioned above can only target cell-surface antigens, and that the range of these antigens is limited, all of these systems are actually circumscribed in both researches and clinical trials.
To break the limitation, we decide to develop a cell-therapy transducer system that is able to recognise free ligands. By importing a totally orthogonal signal transducer, we successfully extend the range of recognisable tumour markers to both cell-surface and free antigens.

To demonstrate our work, we choose non-small-cell lung cancer (NSCLC) for a specific case of application. NSCLC morbidity has been increasing to top in the world these years, occupying 85% of diagnosed cases of lung cancer5. However, screening for NSCLC by CT has a high misdiagnosis rate, not to mention the fact that the relapse rate and mortality are both considerably high. As a consequence, it's urgent for us to develop a new method for its treatment.
We want to find certain antigens to indicate development of NSCLC. And the first one, vascular endothelial growth factor (VEGF), is a broad-spectrum tumour marker, with the sensitivity to NSCLC of 85%5. By representing the level of angiogenesis, which is a critical stage for tumour to develop and metastasis, VEGF can be a reliable indicator for lung cancer.

85% sensitivity is ideal, but still not enough. That's why we also look at a more straightway marker, D-Dimer. Being the smallest fragment from degradation of fibrous protein, D-Dimer can be an ideal indicator of NSCLC development6, thus help us to design a cell therapy treatment to prevent NSCLC from relapse.

By recognising VEGF and D-Dimer, our system – the Synthetic Transducer Engineering Platform (STEP) – can be activated for treatment of NSCLC. The detailed design and its application can be viewed in the project design and applied design pages.
References
[1]Kochenderfer, J. N. et al. Long-Duration Complete Remissions of Diffuse Large B Cell Lymphoma after Anti-CD19 Chimeric Antigen Receptor T Cell Therapy. Mol. Ther. 25, 2245–2253 (2017). [2]Felder, M. et al. MUC16 (CA125): tumor biomarker to cancer therapy, a work in progress. Mol. Cancer 13, 129 (2014). [3]Cho, J. H. et al. Engineering Axl specific CAR and SynNotch receptor for cancer therapy. . Sci Rep 8, 3846 (2018). [4]Rapoport, A. P. et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat. Med. 21, 914–921 (2015). [5]Lai, Y. et al. Serum VEGF levels in the early diagnosis and severity assessment of non-small cell lung cancer. J Cancer 9, 1538–1547 (2018). [6]Jiang, H.-G. et al. Value of fibrinogen and D-dimer in predicting recurrence and metastasis after radical surgery for non-small cell lung cancer. Med. Oncol. 31, 22 (2014).

  Address


G604, School of Life Sciences, Fudan University
2005 Songhu Road, Yangpu, Shanghai, China