BRONZE

Cytotoxic T-Cell Implantation & Genetic Modification in a Treatment for Lung Carcinoma

A self designed theoretical treatment for Lung Cancer using Cytotoxic T-Cell implantation and genetical modification.
Ayush Chalishajar
Grade 8

Problem

Problem

The problem that I am tackling is the lethality of Lung Carcinoma (Lung Cancer). Although Lung Cancer can be treated by medications and complicated surgeries or therapy, these methods do not always provide positive or satisfactory results. The question remains how can we treat such a lethal disease more efficiently, at a lower cost, and with fewer side effects using external Cytotoxic T-Cells? 

Hypothesis

T-Cells are a crucial component of our bodies fighting against any disease. I believe that implanting genetically modified Cytotoxic T-Cells (that have already targeted Lung Cancer) into patients will allow the body to fight the disease more efficiently and faster. Naturally, our body takes a long time to create antibodies to fight against any disease and by then the severity usually escalates. With artificial implantation, antibodies can be introduced faster which will start fighting the disease almost instantly, allowing more efficient treatment. This would result in fewer effects on the patient from the disease and potentially reduce mortality rates.
 

Background Research

Lung Carcinoma - Abstract

Lung Carcinoma is cancer that affects the lungs (Lung Cancer), resulting in many health complications such as difficulties in breathing and coughing up blood. About two million people are diagnosed with this disease yearly and will continue to get diagnosed in the future. When a person has Lung Cancer, they have abnormal cells that cluster together to form a tumour in the lung. These cancer cells grow without order or control, destroying the healthy lung tissue around them. Lung Cancer usually spreads through the body quickly, resulting in most people with this disease developing cancer in other parts of the body. Current treatments have shown to have minimal impact, as Lung Cancer still has the highest death rate compared to other cancer. For this reason, Lung Cancer requires a new advanced treatment, which will work more efficiently and have fewer complications. Considering the ethical factors and having full awareness about this, this treatment is completely HYPOTHETICAL.

Types of Lung Cancer

Small Cell Lung Cancer (SCLC)

  • 15% to 20% of all lung cancers are SCLC 
  • Cancer cells are smaller and harder to target and treat
  • More aggressive form of lung cancer; cancer cells tend to grow quickly and travel to other parts of the body, or metastasize, more easily.

Non-small Cell Lung Cancer (NSCLC)

  • 80% to 85% of lung cancers are NSCLC. 
  • Emanates from lung tissue
  • Easier to treat than SCLC
  • Usually grows and spreads to other parts of the body more slowly than SCLC does

Causes of Lung Cancer

  • Smoking -  tobacco products can increase the risk of Lung Cancer because tobacco smoke is made up of chemicals, many of which are poisonous.
  • Secondhand smoking - despite being indirect, secondhand smoking can still cause Lung Cancer because of the inhalation of the smoke.
  • Radon - natural gas produced when uranium, radium and thorium break down within the ground. It seeps through gaps in homes and buildings, it is the main cause of Lung Cancer in non-smokers.
  • Family history - If your blood parents or sibling has or does have Lung Cancer, it is likely that it will be passed on to you as well, as well as your offspring.
  • Radiation therapy - survivors of cancer who’ve had radiation therapy, specifically to the chest, have a higher risk of Lung Cancer.
  • Diet - scientists have noticed that smokers taking beta-carotene supplements have an increased chance of Lung Cancer, despite beta-carotene having various benefits.
  • Other substances - exposure to asbestos, arsenic, diesel, exhaust, and some forms of silica and chromium can cause Lung Cancer because they are carcinogens (promotes cancer), these substances can be found in various workplaces

Symptoms of Lung Cancer

Lung Cancer can come with many symptoms, including:

  • Cough that won't go away
  • Losing weight unintentionally and loss of appetite
  • Shortness of breath
  • Chest and shoulder pain
  • Coughing up blood, even a small amount
  • Hoarse voice
  • Headaches
  • Pain in your bones
  • Lack of energy
  • Face and neck swelling

Effects of Lung Cancer on the body

Although Lung Cancer is cancer that begins in the cells of the lungs, it is known to spread to other parts of the body. In the later stages of Lung Cancer, especially if it spreads to distant areas, it can affect many systems of your body making it harder to treat. This process is called metastasis. Lung Cancer tends to spread to the lymph nodes, bones, brain, liver, and adrenal glands. Initially, it affects only the lungs and respiratory system. Other symptoms vary depending on where cancer migrates.

  • Respiratory system - can cause intense coughing, shortness of breath, nearby tumours, and fluid accumulation around the lungs
  • Circulatory/cardiovascular systems - can cause blood clots, bleeding arteries, and heart cancer
  • Immune/excretory systems - can cause lymph node and liver cancer
  • Central nervous system - can cause headaches, neurological issues, and brain cancer
  • Skeletal/muscular systems -  can cause bone/muscle pain and weakened bones

 

Current Diagnostics

Lung Cancer can be detected by several common tests, such as:

  • Biopsy - small sample of tissue is taken from the lung/nearby lymph nodes to be examined
  • Chest X-ray - produces clear, detailed images of your lungs
  • CT scan - creates a series of cross-sectional X-ray images of your lungs
  • MRI - uses magnetic-field technology to detect and identify tumours
  • Bronchoscopy, which involves the use of a tube with an attached camera and light to view your lungs and other structures
  • Sputum Culture - use to analyze the liquid substance produced by your lungs when you cough
  • Screening test for Lung Cancer - use for patients who have a higher chance of developing lung cancer

Current Treatments

Lung Cancer is treated in several ways, depending on the type of Lung Cancer and how far it has spread. People with Non-small Cell Lung Cancer can be treated with surgery, chemotherapy, radiation therapy, targeted therapy, or a combination of these treatments. People with Small Cell Lung Cancer are usually treated with radiation therapy and chemotherapy.

  • Surgery: An operation where doctors cut out cancer tissue.
  • Chemotherapy: Using special medicines to shrink or kill cancer. The drugs can be pills you take or medicines given in your veins, or sometimes both.
  • Radiation therapy: Using high-energy rays to kill cancer.
  • Targeted therapy: Using drugs to block the growth and spread of cancer cells. The drugs can be pills you take or medicines given in your veins.

Why is a new treatment needed?

Although there are already various treatments that are used to treat Lung Cancer, there are still many issues.

  • The survival rate is still lower than any other cancer being only 18.6%. More than half of the people with lung cancer die within one year of being diagnosed. 
  • Current treatments tend to have many side effects, such as; hair loss, weak immune systems, nausea, etc.
  • Takes lots of time and money, with no guaranteed efficiency

Due to these issues, a  more advanced treatment is needed that will not only be effective but efficient, meaning that it will not take tons of time and money, have fewer side effects, and have a higher success rate. 

What T-Cells?

T-cells are a part of the immune system that focuses on specific foreign particles. Rather than generically attack any antigens, T-cells circulate until they encounter their specific antigen. As such, T-cells play a critical part in immunity to foreign substances. There are 3 main types of T-cells: 

  1. Cytotoxic - kill virally infected cells and tumours
  2. Helper - help other cells of the immune system fight off diseases/illnesses
  3. Regulatory - shut off the immune response to prevent damage to normal cells

Although the most common context of T-cells in infectious diseases, they are used for other aspects of adaptive immunity too. This includes responses to 

  • Allergens (allergies)
  • Tumours (cancers)

Cytotoxic T-Cells

Cytotoxic T-cells are the main immunity response our body has against any illness/disease. They are a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected (particularly with viruses), or cells that are damaged in other ways. 
Most cytotoxic T-cells express T-cell receptors (TCRs) that can recognize a specific antigen. An antigen is a molecule capable of stimulating an immune response and is often produced by cancer cells or viruses. 

  1. Antigens inside a cell are bound to class 1 MHC molecules and brought to the surface of the cell by the MHC molecule, where they can be recognized by the T-cell. 
  2. If the TCR is specific for that antigen, it binds to the MHC molecule and the antigen, and the T-cell destroys the cell.
  3. Although the main function of Cytotoxic T-cells is to kill virally infected cells, they also kill cells with intracellular bacteria or tumorous cells.

Apheresis

Apheresis is a medical procedure. It involves:

  1. Removing whole blood from a donor or patient 
  2. Separating the blood into individual components so that one particular component can be removed
  3. The remaining blood components are reintroduced back into the bloodstream of the patient or donor. 

Apheresis is very useful for creating vaccines and other antibodies against diseases, as it allows us to target very specific components in the blood such as the disease cell itself or antibodies our body has created already.

Genetic Modification

In recent years many scientists have started looking into cell-mediated immunity and its possibilities. One of the more prominent focuses is T-Cells. T-cells play a key role in cell-mediated immunity and strategies to genetically modify T-cells either through:

  • Altering the specificity of the T-cell receptor (TCR) 
  • Introducing antibody-like recognition in chimeric antigen receptors (CARs) 

These methods have made substantial advances in cell-mediated immunity. One of these advancements is that with these methods, regular T-Cells can be modified to target specific diseases and have a stronger impact in fighting the disease. 
 

Method

Cytotoxic T Cell Therapy (CTT)

Treatment Description

My idea is to create a theoretical treatment (Cytotoxic T-Cell Therapy) for Lung Cancer (Lung Carcinoma). This theoretical treatment procedure would use the external implantation of genetically modified Cytotoxic T-Cells into a battling patient’s immune system, allowing the patient to fight the disease more effectively. These T-Cells would be extracted from the patient using apheresis, and then genetically modified to have TCRs for Lung Cancer. They would later be implanted into the battling patient’s system. Since T-cells already have TCRs for Lung Cancer on them, they will be able to easily recognize and fight the disease. With the help of these “enhanced” T-cells, it will allow the patient to fight the disease more easily compared to other treatments that are known to have side effects, expensive, and often not be efficient.
NOTE*: This treatment is completely hypothetical and has never been implanted before.
NOTE**: This treatment is inspired by the method to use T-cells in vaccine creation.
NOTE***: This treatment is only to be used in the later stages of lung cancer as other treatments are shown to be efficient in earlier stages.

Procedure

  1. Evaluation: Patients undergo a series of tests and screenings to determine if this procedure is an appropriate option.
  2. Collection: If deemed appropriate, Cytotoxic T-cells are collected from the patient via apheresis. The remaining blood is then returned to the body.
  3. Engineering: The T-cells are sent to a laboratory where they are genetically modified to have TCR (T-cell receptors) on their surface. 
  4. Multiplication: The genetically modified T-cells are "expanded" by growing cells in the laboratory until there are millions of them. This process can take a few weeks. When there are enough T-cells, they are frozen and sent to the hospital or center where the patient is being treated.
  5. Infusion: Patients are admitted to the hospital and the T-cells are re-infused in a process similar to a blood transfusion. This is a one-time infusion, although patients may remain in the hospital under observation for several weeks to monitor response to treatment, overall condition, and side effects.
  6. Treatment Process: Over the following weeks, T-cells will circulate through the system and attack tumours, killing the tumour/cancer cells.

Materials

This theoretical treatment requires a few materials including:

  • Apheresis machine - for the apheresis process
  • Cytotoxic T-cells - extracted from the patient's body, most crucial part of treatment 
  • TCRs - inactive Lung Cancer viruses will be introduced to the T-cells, resulting in TCRs being introduced to the surface of these cells
  • Laboratory - where T-cells will be introduced to TCRs and be multiplied
  • IV - using a blood bag containing these modified T-cells, the IV system will help the T-cells to enter the body

Analysis

Side Effects:

As with any treatment, CTT will have some side effects too. Some of them include:

  • Cytokine overload - When T-cells communicate with each other, they do so using chemicals called cytokines. When the body’s immune system goes into overdrive, it can trigger a cycle of releasing lots of these cytokines, which in turn can activate more white blood components. This can cause headaches, respiratory issues, fevers, and even death. In the unlikely event that this occurs, this can be dealt with with drugs or therapy which are shown to have a high success rate.
  • Tumour lysis - When the T-cells kill the tumour cells, these then break into parts and the leftover can be floating in your bloodstream. If there were too many tumour cells, the body can’t process the waste components, and the blood is “poisoned” (gout). Can be treated with medication like Allopurinol and Febuxostat (anti-gout medication).
  • Flu - Due to the cytokine response, the immune system is weakened, resulting in flu symptoms (fever/chills, sniffly nose, achy joints, etc.). This is normal and supports that the treatment is working

Cost:

Knowing the cost is a major factor that affects many people around the world, this treatment needs to be affordable and feasible to a larger number of people.

  • Apheresis costs approximately $3000 including the materials and doctors fee
  • T-cell modification and multiplying will cost approximately $50,000, depending on the laboratory
  • Blood transfusion costs between $500 - $2000
  • Checkups and hospital monitoring costs will vary depending on the hospital but can be estimated to cost $20,000 for 2 weeks in the hospital.

In total, the entire process can be estimated to cost $75,000. Although this seems like a large amount, it is a one-time treatment, making it relatively cheaper than its alternatives. This price obviously can vary due to other factors, such as complications, insurance, and hospital charges. The cost will most likely change in the future as technology advances, making T-cell modification cheaper. 

Why is it better?

Although this treatment is completely hypothetical, it still shows a lot of promising benefits. 

  • Cost - Compared to other current treatments for Lung Cancer (chemotherapy - approx. $12,000 a month), CTT is relatively cheap, being a one-time treatment at a relatively low cost. This means many more people will be able to afford it, creating a feasible treatment option for Lung Cancer.
  • Efficiency - Due to this being a one-time treatment, it is a short process that should theoretically have a very high success rate. This makes it very appealing to cases that are getting treated in the later stages.
  • Side Effects - Although CTT has some side effects, it is still a better option than other treatments such as immunotherapy which has more severe side effects.

Pros vs Cons:

There are always pros and cons to every medical procedure, including this one.
Pros:

  • Not invasive - unlike other treatments, CTT would not be invasive, harming healthy parts of the body as the T-cells are targetted for lung cancer cells
  • Minimal side effects - although side effects are present, they are minimal and have very low lethality,
  • Cheap/affordable - CTT is relatively cheap compared to other Lung Cancer treatments such as chemotherapy, which cost more than $10,000 a month
  • Efficient - CTT is a one-time treatment, meaning it should be efficient and will not take many months to take effect

Cons:

  • Unknown risk factors - since CTT has never been implanted, we don't know what potential risks could be caused by it, making it less reliable
  • Potential immune system rejection - there is a chance of the body may not adopt the T-cell, meaning it would reject the treatment and fight against it.
  • Side effects - although the current potential side effects are minimal, there is a large chance of more side effects being presented when applied, which could greatly escalate
  • Challenges -  Since CTT is a theoretical treatment, there is a very high chance it may not work or more complications may come up at the trial stages.

 

Conclusion

Conclusion

Lung Cancer is a highly lethal cancer that has very severe and devastating symptoms and effects, greatly impacting the body and often resulting in death, despite various current treatments. If Lung Cancer can be treated using cytotoxic T-cells and genetic modification, this can be a good long-term treatment option. Creating Cytotoxic T-Cell therapy should show very promising results (if applied) due to the non-invasive approach and minimal side effects. Having considered the pros and cons, the treatment is very beneficial in the long run, having many benefits (low cost, minimal side effects, few materials, efficiency, etc.) with minimal cons. In conclusion, if the concepts of this treatment are applied, it will theoretically show full validity from using apheresis to extract cytotoxic T-cells, introducing TCRs to these cells and multiplying them in a lab, and then introducing these cells back to the bloodstream.

What’s Next?

Having applied Cytotoxic T-cell therapy to Lung Carcinoma has inspired me to see if this treatment has even more potential than already theorized. Knowing how devastating and damaging it is to a cancer patient and their family to experience such a thing, I thrive to increase awareness on the lethality of cancer and the effect it has on patients.  I plan to further look into the topic to introduce more benefits of CTT and how this innovation can be applied, not only in lung cancer but many diseases in general. 
 

Citations

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Acknowledgement

I would like to acknowledge the assistance of a few people with my project.

  • Firstly, I would like to acknowledge my parents for their support and help throughout my project. They helped me with editing and provided feedback, which allowed me to improve my project.
  • Second, I would like to acknowledge my teachers, Ms. Brooks and Ms. Spencer, for their feedback and guidance.  They provided me with feedback that helped me make my project better.
  • Lastly, I would like to acknowledge Dr. Randeva for his input on my project idea. He gave me advice on potential issues that may come up with this treatment.