Team:CPU CHINA/HP/Silver

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Silver

Summary

Our team aims to fully exploit our university’s advantage in pharmaceutical science to design an effective treatment of a disease. By comparing the data collected, we chose rheumatoid arthritis and other refractory autoimmune diseases for our project. Conducting thorough field studies and understanding the current clinical status of rheumatoid arthritis were very important to our design and optimization.

Survey data

Rheumatoid arthritis (RA) is a chronic inflammatory disease that may exhibit chronic synovitis, synovial hyperplasia and fibrosis, mononuclear cell infiltration, synovial fluid T, B lymphocytes and plasma cells, increased collagenase, etc. It’s a chronic disease with high morbidity. There are several new therapies that have been used for the treatment of RA, but due to low awareness and low recovery rate, many patients fail to receive a proper treatment in RA’s preliminary stage which not only afflicts the patients, but also brings a heavy financial burden to their families.
In China, the prevalence of rheumatoid arthritis is 0.2% -0.4%, so with a population of 1.3 billion, China's rheumatoid arthritis patients are expected to be around 5 million. If they cannot be given effective treatment, their mobility will be limited due to joint pain, and will eventually lead to disability. Statistically, disability rate in patients with two years of rheumatoid arthritis is up to 50% while those with three years can be 70%.

Field Studies

To further understand the patients' conditions and the clinical status of treatment, we decided to go to Nanjing Gulou Hospital and Nanjing First Hospital to perform a questionnaire survey in the department of rheumatology immunology after beforehand investigation and contact. First is our preparation:

Respondents: patients with rheumatoid arthritis at inpatient and outpatient in rheumatology department
Sample Size: 80 people
Procedure:
1. The production of questionnaire (Avoid sensitive issues and patients’ personal information, and respect patients for their personal privacy).
2. Assign teammates with different tasks.
3. Determine the procedure and the time.

With our planned schedule, we went to the hospital for a two-day survey (Figure 1). We ensured the authenticity of the answers to our questionnaires. For patients with reduced mobility, our members completed the questionnaire according to their oral narration (Figure 2). We tried to gain more insights in the treatment they expected to receive, as well as the treatment they received in real life, which enabled us to feel more about the pain and suffering this disease could bring.

Figure 1. Conducting a questionnaire in the Nanjing First Hospital

Figure 2. Our teamer was talking with the patient carefully

Questionnaire analysis

The following conclusions can be drawn by analyzing the data collected from the questionnaire statistically (Figure 3-5 are part of the questionnaire data) together with some supporting materials:
Rheumatoid arthritis is a disease most commonly seen in women aged 40-60 years old, so it is a typical middle-aged and old-aged disease, which seriously affects patients' life quality. Most patients choose drug treatments to alleviate the pain, but in actual clinical practice all currently available drugs fail to show any very significant therapeutic effect, which is why patients crave for new treatment methods. They also hope that the new method can have less side effects and lower recurrence rate, thereby reducing their pain. In addition, rheumatoid arthritis can also increase the burden on the national economy. The United States has once carried out an epidemiological survey, showing that annual cost on rheumatoid arthritis and rheumatoid-related treatment is more than 1% of its GDP. Though there is no such exact data in China, it is estimated that the financial loss caused by this disease is not less than the United States. As the aging problem becomes increasingly prominent, this national economic burden will become more and more heavy. If a new treatment can be designed to cure this disease radically, it will be of great significance in promoting public health and people’s health conditions.

Figure 3. The treatment effect and gender of patients The treatment effect and gender of patients

Figure 4.  The impact on patients’life and work after diagnosed with RA

Figure 5.  The existing treatment methods

Figure 6.  Chimeric Antigen Receptor T-Cell Immunotherapy

Finding new treatments

CAR-T, short for Chimeric Antigen Receptor T-Cell Immunotherapy, is a chimeric antigen receptor T cell immunotherapy. This is a new cytotherapy that has existed for many years but hasn’t been used clinically until some recent improvement. Similar to other immunotherapies, its basic principle is to use the patient's own immune cells to specifically remove cancer cells. As shown in Figure 6, T cells are differentiated and enriched by in vivo injection of cytokines, and then the target cells are separated by cell surface markers. Next, the cells are engineered in vitro with CAR (Chimeric Antigen Receptor), and are amplified by cell culture to a certain number before returned to the patient's body. In this way, the engineered T cells can kill the target cells specifically in vivo.

Syn-Notch CAR-Treg cytotherapy

We discussed how to design a treatment for rheumatoid arthritis during our group meeting (Figure 7) and with our advisor in depth. Eventually, based on traditional CAR-T, we chose Treg cells as engineering targets in the purpose of curing rheumatoid arthritis, and we innovatively introduced a Syn-Notch system to enhance the stability of the engineered Treg cells in vivo. We came to form a new Syn-Notch CAR-Treg system (the overall idea shown in Figure 8) after some optimization on our design.

Figure 7. Routine group meeting

Figure 8. The global design of Syn-Notch CAR-Treg system

Retrospection of Survey

With a deeper research on treatment methods, the feasibility was verified at experimental level. But it still had a long way to go before it can be applied clinically. With our first survey results and some questions, we went to the hospital again, and conducted another questionnaire survey and interviewed some residents (Figure 9).
Preparatory work:
    Respondents: patients and doctors with rheumatoid arthritis at inpatient and outpatient of rheumatology department
    Sample size: 30 doctors and 80 patients
    Procedure:
         1. List a questionnaire for patients and doctors (Avoid patients’ and doctors’ personal information).
         2. Assign teammates with different tasks.
         3. Contact relevant departments of the hospital.
         4. Determine the process and the time.

Figure 9. Go to the hospital for in-depth investigation again

According to our plan, we came to Nanjing First Hospital and Nanjing Gulou Hospital for a questionnaire survey. The majority of patients showed great interests in our innovative therapy and explored the specific way of using this therapy after a conversation with them. Some patients were confident in our treatment and encouraged us to make more efforts in getting this therapy into clinical as soon as possible (Video 1). According to the survey, most of them have suffered from RA for more than 5 years. It was gratifying to note that more than half of the patients said they were willing to try Syn-Notch CAR-Treg cell therapy while others showed some uncertainty (Figure 10). But we believe this therapy will be more recognized with more future research.

Figure 10. Patients’ willingness to try syn-Notch CAR-T cell therapy

Video 1. We conducted detailed interviews with the patient

As for our survey with the doctors, most of the them have worked for more than 5 years (Figure 11), and they believed that the current drug treatment had shortcomings like severe side effects, a high recurrence rate and a chronic medication use (Figure 12), while Syn- Notch CAR Treg cell therapy had a more specific target and may show less side effects (Figure 13), which surpassed the existing treatment. Its safety was also further recognized by healthcare professionals. However, there are many problems remaining to be solved before it can actually be applied clinically(Figure14), such as a limitation on large-scale production, quality control standards, etc.

Figure 11. Doctor working years

Figure 12. The shortcomings of existing treatment（Multiple choice)

Figure 13. The advantages of CAR Treg cell therapy (multiple choice)

Figure 14. The CAR Treg cell therapy will face the challenges for applying to clinic (multiple choice)

Reference

1.Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia. Sci Transl Med. 2014; 6(224):224ra25.

2. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. The New England journal of medicine. 2014; 371(16):1507–17.

3. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015; 385:517–28.

4.Lubbd VD, Dijikmans BAC ,Markusse HM , et al.Lack of clinical effect of CD3 McAb therapy in early RA:a placebo , controlled trial.Arthritis Rheum , 1995 ;38 :1097

5.Choy EHS , Pitzalis C , Cauli A , et al.Percentage of anti-CD4 monoclonal antibody coated lymphocytes in the rheumatoid joint is associated with clinical improvement.Arthrit is Rheum, 1996 ;39 :52

6.Moreland LW, Sewell K , Trentham DE , et al.IL-2 diphtheria fusion protein in ref ractory RA:a double blind placebo control trialwith open label extension.Arthritis Rheum , 1995 ;38:1177

7.Mu H, Charmley P ,King MC, et al.Synergy between T cell receptor β gene polymorphism and HLA-DR4 in susceptibility to RA.Arthritis Rheum , 1996;39 :931