Engineering your Body to Kill Cancer
How does CAR-T Cell Therapy work, and what’s next?
We may be in the midst of a major inflection point right now in cancer therapy. The field of cancer immunotherapy asks how can we use the tools our immune system deploys to fight infections, and see how we can re-engineer them in the fight against cancer.
In our lifetime, we may see the terms “Chemo” and “Radiation” get replaced by words like “T-Cell”, “Checkpoint Inhibitors” and “Antibodies” as the cancer-killers everyone’s talking about.
The best part about all of this? Cancer immunotherapies are already helping patients with relapsing cancer, and the patient’s with drug-resistant cancers!
But let’s rewind the clock. You’ll notice that something isn’t right if you look at the leadup in cancer therapy up to right now…
Interfere and Anhialate
Imagine if you got diagnosed with Leukemia tomorrow morning. Some of your white blood cells have gone rogue and are threatening your life by dividing uncontrollably and by failing to fulfill their roles in the immune system.
What are your options?
If you are detected early enough for treatment to be effective, you’ll likely be faced with 2 therapies, if not both as a combination:
- Blasting your tumor cells with different frequencies and angles of applied radiation to destroy them.
- Poisoning your cancer’s tumor cells with chemotherapy drugs so that they can no longer divide at all.
This is the standard toolkit that we’ve been using since 1901, for radiotherapy, and the 1940s, for chemotherapy. It’s no secret that this almost 80-year-old approach erodes the quality of life for most cancer patients, chipping away at their health over time.
The problem is that it’s been mostly small, incremental changes are what separate our cancer treatment pipelines today from back then. We’ve been in a long ~70-year wait since we’ve last seen a scalable paradigm shift in how we approach treating cancer!
The never-ending battle
Your body is always at war, and that’s not an understatement.
In fact, your body’s immune system is the greatest war hero ever! Throughout your lifetime, your immune system will fight millions of nasty viruses, bacteria, and toxins. All of these disgusting things are constantly attacking you, trying to enter your body and make you their home.
If your immune system is an army keeping you between life and death, cancer would be a surprise mutiny from the cells that are supposed to help your body.
Your personal army
The immune system is tasked with defending your body from invaders and foreign threats- just like an army stationed to defend a city from an invading enemy force.
Your defenses begin with a giant wall: the skin. This does a fantastic job at physically shielding your body’s internal systems from a very germy outside world.
However, walls don’t work all the time and when a pathogen breaches your body’s outer perimeter, the battle is on! When a pathogen penetrates or grows in your body it’s now an invading threat, and your body doesn't take kindly to those.
Now that the invaders are here, your immune system has an array of different immune cells which get deployed in waves of attacks:
- Front Line Soldiers (Phagocytes): Macrophages and Neutrophils
- Backup Soldiers: Natural Killer Cells
- Special Forces (Lymphocytes): T-Cells and B-Cells
Skin, Phagocytes, and Natural Killer Cells all do a solid job at stopping and then remembering most pathogens you’ll face in your lifetime. However, sometimes the invading force is too strong and you need to call in the last resort- the special forces.
When situations get out of hand, the immune cells’ elite forces, T-Cells and B-Cells (aka. Lymphocytes) are deployed into the battle. Cancer is one of these threats that present the need for your lymphocyte elite forces to be called in.
The lymphocytes keep track and respond to pathogens by detecting a specific pathogen's antigens. Antigens are molecules which act as chemical “fingerprints” of specific pathogens. Antigens can be floating around the body or can be found on the surface of a pathogen or cell infected by the pathogen.
The lymphocytes use special receptors on their cell surfaces that can pick up and bind to specific antigens like a lock-and-key.
Since there are billions of different antigens, most of your body’s billions upon billions of lymphocytes each have a different antigen receptor on their surfaces. Antibodies also work like this, where a new antibody needs to be built for every new antigen in the body.
When a lymphocyte’s receptor matches a disease antigen, that specific cell will instantly start cloning itself and call for familiar backup.
If all the diseases and their antigens present themselves like a billion single-key doors, your body follows up with a billion corresponding keys!
When looking at more effective ways to deal with certain cancers, we’ll be specifically focusing on your T-Lymphocytes (aka.T-Cells).
Breaking down T-Cells
T-Cells get their name from the thymus- a specific gland that the T-Cells travel to in order to mature and develop. These cells make up the last-ditch waves of attack that your immune system deploys for serious threats.
T-cells themselves also come in different classes, each with unique immune system roles:
- Cytotoxic (CD8+) T-Lymphocytes
- Helper (CD4+) T-Lymphocytes
- Regulator (CD4+) T-Lymphocytes
- Natural Killer T-Lymphocytes
- Memory T-Lymphocytes
The T-Cells will commit to these specific sub-categories or “lineages” as they mature in the thymus. The more a T-Cell becomes committed to a lineage, the more they resemble one of the above categories.
Think of this as how trainees for a SWAT team wouldn’t join already specialized, rather they’d train to become a sniper, engineer, commando, etc. The SWAT trainees would learn to individually specialize down the road.
CAR-T cells 101
With the help of genetic engineering tools, T-cells can be re-engineered to efficiently kill tumor cells in patients who need it the most! These include patients who have relapsed or treatment-resistant (aka. refractive) white blood cell cancers.
Engineering CAR-T cells
Hematological malignancies are a category of cancers from the cells responsible for developing blood. These include cancers like Leukemia, Multiple Myeloma, and Lymphoma, all of whom have antigens that are pretty consistent between patients with the same type of cancer.
A good example of this is the CD19 molecule, which is an antigen associated with B-Cell Acute Lymphoid Leukemia (ALL). Once we select an antigen like CD19 for B-Cell ALL, we can go on to introduce genes for engineered receptors in a T-cell.
The genes then develop a receptor on the cell surface, designed to read and bind to the specific cancer antigen. These cancer antigen-matching receptors are called Chimeric Antigen Receptors (CARs).
Just like a regular T-cell receptor, CARs for any specific antigen need their own unique gene. Once we have the gene, it can be introduced to the T-Cell through a virus (viral vector) or through gene editing tools like CRISPR Cas9.
When the T-Cell starts expressing the gene for its specific Chimeric Antigen Receptor, it can activate its final form: a full-on CAR-T Cell!
These CAR-T cells would then target tumor cells with the antigen in the body, carrying out different functions depending on what T-Cell linage they fall under.
Through this process, we have an incredibly effective therapy model for patients with drug-resistant or relapsed white blood cell-based cancers.
With all this said and done CAR-T Cells may seem like a distant vision for treating a few types of cancers, but the FDA sees a different story!
FDA approved and on the market
In 2017, two CAR-T cell therapeutics: Kymriah and Yescarta were approved for treating patients with B-Cell Acute Lymphoid Leukemia and B-Cell Lymphoma respectively.
Yescarta and Kymriah target antigens commonly associated with their target cancers, both working with the “CD19” antigen in different tumor environments. This CD19 antigen is associated both with B-Cell Lymphoma and B-Cell Acute Lymphocytic Leukemia.
CAR-T Cell therapy is being developed and innovated upon on a growing scale and it’s here to stay. Yet with all that said and done, we’ve still got a long way to go and many questions to answer…
The unanswered questions
The development of CAR-T Cells into effective cancer immunotherapies is going to have us answering key questions in the coming years, both involving the science AND economics of it all.
I’m going to be covering each of these problem areas in my CAR-T article series throughout this summer, and I’ll indicate what specific part of the series will dive into the problem as we go along. (Shameless plug)
Right now the main issues we’re looking at boil down to risk, scale, and expansion.
T-Cells are a risky therapy
The scaling up of cancer immunotherapy drugs like CAR-T is happening, and they’re relatively more effective than other cancer drugs. Yescarta and Kymriah yielded 80%-83% cancer remission rates with no relapse, in cases of children who had their cancers relapse when previously on chemotherapy.
However, this effectiveness comes with higher risks for patients on T-cell therapeutics. Sometimes T-Cells can get too good at their job and start killing your body’s own cells.
This can happen in the form of Graft-versus-Host Disease (GVHD), where a T-Cell detects its target antigen on healthy cells rather than on a pathogen. This can lead the T-Cells to destroy your body’s own healthy cells with the same antigen, even if the antigen is in little abundance there.
Mishaps like this have lead to deaths in T-Cell therapy, which proves a constant reminder to question and evaluate these therapies down to a literal “T”.
In Part 3 of the series, I’ll cover new strategies being used to mitigate this over-reactiveness of some T-cell therapies.
We can only get 20% of Cancers
The current use cases for CAR-T Cell therapies have all been for cancers of white blood cells. CAR-T cell therapies work better here due to the fact that these cancers consistently have the same antigens associated with them.
The next meaningful step for CAR-T Cell therapy is to expand it for the remaining 80% of cancers: the solid-state tumors. Solid state tumors include most of the notable killers: lung cancer, breast cancer, pancreatic cancer, glioblastoma, etc.
The science behind expanding CAR-T cell capabilities for solid tumors is an entire PhD-worth of content, which we’ll cover in Part 2 of this CAR-T cell series.
CAR-T cells are ridiculously expensive
Right now the costs for Yescarta and Kymriah are labeled at $373,000 and $475,000 respectively per patient. We can blame this heavy price on the currently inefficient ways of developing T-cell therapies right now.
Currently, the common practice is to:
- Extract a patient’s T-cells from their body
- Genetically engineer the T-Cells to express the gene for a CAR
- Give time for the T-Cell to activate the CAR and become a CAR-T Cell
- Reintroduce the patient’s CAR-T Cells into their body.
This entire process is long, inefficient, and crazy expensive. Scaling up the production of T-cells for lower costs is going to be one of the most crucial questions to answer for the future of CAR-T Cell therapy.
Scaling up the economics of CAR-T cells will ideally let the masses of patients who require special treatment, to be able to access it. We’ll also cover how to scale-up this T-Cell production process in Part 2 of the series.
Cancer immunotherapy is looking to pick up the slack from its chemotherapy and radiation predecessors. By training the human immune system to detect, kill and remember certain cancer types just like it would for the flu, we have a shot at bringing a new juggernaut therapy for cancer to fruition!
- CAR-T Cell Therapy is the process of re-engineering your body’s T-Lymphocyte cells to destroy tumor cells for certain cancers.
- There are 2 CAR-T Therapeutics out in the market as of June 2019: Yescarta and Kymriah
- CAR-T Cell Therapies are very expensive! For one patient, Yescarta and Kymriah cost $373,000 and $475,000 respectively.
- The future steps for CAR-T Cell therapy will be around making it more affordable, and able to treat solid-state tumors.
It may be the case that this immune cell re-engineering may be a viable future treatment that’s better for patients than poisoning their cells with chemotherapy drugs or destroying tissue with radiation therapy.
Maybe one day with the help of cancer immunotherapy, we can make dying from cancer a cringeworthy historical past-tense like dying from smallpox.
Disclaimer: I am currently helping with T-Cell development research. Therefore this perspective is inclined to bias and will not be 100% Objective.
- Khymriah: https://en.wikipedia.org/wiki/Tisagenlecleucel
- Cancer and the immune system: https://www.cancerresearchuk.org/about-cancer/what-is-cancer/body-systems-and-cancer/the-immune-system-and-cancer
- Graft-Verus-Host-Disease: https://www.llscanada.org/treatment/types-of-treatment/stem-cell-transplantation/graft-versus-host-disease
- How Chemo affects your Immune System: https://www.breastcancer.org/tips/immune/cancer/chemo
- Immune Evasion in Cancer: https://www.sciencedirect.com/science/article/pii/S1044579X1500019X
- T-cells https://en.wikipedia.org/wiki/T_cell
- Cancer therapy history https://www.cancer.org/cancer/cancer-basics/history-of-cancer/cancer-treatment-radiation.html
- T-Cell proliferation in the body https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678146/
- Properties of CD8+ T-Cells http://www.biology-pages.info/C/CTL.html
- General immunology https://opentextbc.ca/anatomyandphysiology/chapter/21-3-the-adaptive-immune-response-t-lymphocytes-and-their-functional-types/
- T-Cell Commitment https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111953/
- TCR Activation Paper: https://stm.sciencemag.org/content/9/417/eaag1209
- Kymriah Efficacy: https://www.primetherapeutics.com/en/news/prime-insights/2017-insights/Kymriah%20expectations/Kymriah%20expectations.html
- Yescarta Efficacy: https://my.clevelandclinic.org/health/treatments/17726-car-t-cell-therapy/risks--benefits