Team:Nanjing NFLS/Description
Inspiration—How and why we chose our iGEMproject.
Nowadays, cancer is not an unfamiliar word for people. Cancer has a major impact on Chinese society and across the world. It is a large group of diseases characterized by the growth of abnormal cells beyond their usual boundaries, which can then invade adjoining parts of the body and spread to other organs. In 2018, cancer was the second leading cause of death globally and is estimated to account for 9.6 million death.[1] According to statistics from Jiangsu Center for Disease Control (CDC), the incidence and mortality of malignant tumors in China are above average. On a global scale, liver cancer is one of the most common cancer types. In China, there's a saying: 'no wine, no business'. Because of this 'drinking culture' (jiu zhuo wen hua), China is a country with higher incidence of liver cancer: 55 out of every 100 new liver cancer patients in the world are Chinese. In Jiangsu province, liver cancer is one of the most severe malign tumors. Therefore, we decided to continue our exploration of cancer therapy in 2019.
Although the liver cancer situation is serious, there is currently no effective therapy. In April, four members of of team took part in an volunteer activity called ‘Sunflower Children’, which provides assistance and mental support to young children diagnosed with cancer. As tumors in children’s bodies are more homogenized, chemotherapy and radiotherapy are more effective, and thus more intensively implemented. However, these treatments have their price. Most young patients feel extremely painful during such treatments and face the threat of a life-long side effects.
Better alternatives are needed. After subscribing to the organizer's WeChat Official Account, which focused on cancer situation in China and frontline cancer treatment, we came upon many articles on therapy with fewer side-effects and a more promising five-year survival rate: immunotherapy based on neoantigen. It can specifically kill tumor cells throughout the body and be used for both the treatment of tumors and the prevention of repeated metastasis safely. After extensive research and discussion with PI, Professor Ho and doctors,Nanjin g_NFLS finally focused on neoantigen.
Artificial neoantigen—How we selected our project goals.
During the development of cancer cells, many gene mutations will lead to the production of abnormal proteins that are not found in normal tissues. These proteins are likely to activate the immune system and attract the immune system to attack cancer cells. These abnormal proteins are so-called neoantigen. Most patients have neoantigens in their tumors. In general, the more mutations one has, the more neoantigen one carries.
Figure 1. The complex process for personalized cancer vaccines [2]
On July 13, 2017, Nature magazine reported the success of two neoantigen-based personalized tumor vaccines for malignant melanoma.
Professor Carmen Loquai and Professor Özlem türeci from Germany used the neoantigen RNA vaccine to treat 13 patients. After vaccination, all patients developed an immune response against neoantigen. Eight patients with locally advanced surgical treatment had significantly longer recurrence-free survival; the other five patients had advanced malignant melanoma, and 2 of them had a significant tumor shrinkage after vaccination alone; The patient received a vaccine combined with PD-1 antibody treatment to achieve complete tumor remission. [3]
A team led by Professor Catherine J. Wu of Harvard University, using the antigen peptide corresponding to neoantigen as a vaccine, also successfully reported the treatment of malignant melanoma. Six patients received vaccine treatment, four patients did not relapse after 25 months of vaccination, and two patients who had a recurrence, followed by PD-1 antibody treatment, achieved complete tumor remission. [4]
Despite recent advances, many challenges remain in the development of neoantigen vaccines. First, neoantigen is highly individualized, with different neoantigens in different patients, and shared-neoantigen is very rare. Customizing different neoantigen vaccines for each patient is time-consuming and expensive. Second, It is still a great challenge to infer the neoantigen on the basis of in silico predictions of T cell epitopes using cancer exome data. Of the predicted neoantigens, only a minuscule fraction can be shown to be recognized by T cells in patients.
Therefore, we propose to bypass the steps that rely on computer prediction and design an artificial neoantigen as a target for tumor vaccines —the prototype of CITHA.
Project CITHA— How we will achieve our goals.
CITHA refers to ‘Cancer Immunotherapy with Trojan Horse Antigen’. In this project, we introduced the gene of the hepatitis B virus surface antigen (HBsAg) -a non-self protein in the human body- into tumor cells and ensures that it will be selectively expressed on the surface of tumor cells to form the “artificial tumor neoantigen”. This artificial neoantigen could be an ideal target for tumor immunotherapy.
Universality—Why CITHA was a useful application of synthetic biology.
In this project, we are committed to providing new ideas for the treatment of liver cancer according to the principle of synthetic biology. This is an unprecedented attempt, and we expect it would help liver cancer patients. After we discuss with researchers in Jiangsu CDC, we discovered that CITHA’s idea posed great potential in other cancers. In the future, by replacing tumor-specific promoter and ‘Trojan Horse’(HBsAg), our CITHA’ could be used as targets in different cancers, including melanoma, lung and cervix cancer, thereby serving as a novel cancer treatment application in today’s dilemma..
References
[1] https://www.who.int/health-topics/cancer#tab=tab_1
[2] Vormehr M et al. Mutanome directedcancer immunotherapy. Curr Opin Immunol. 2016 Apr;39:14-22. doi:10.1016/j.coi.2015.12.001.
[3] Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017 Jul 5. doi: 10.1038/nature23003.
[4] An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017 Jul 5. doi: 10.1038/nature22991.