Expanding the Cancer Therapy of the Future
How can we get CAR-T Cell Therapy Working in Solid Tumors?
Finding a cure to cancer- it seems promising yet really idealistic at the same time. This awesome moment will likely come in the coming decades, but it won’t be in the form of a magical silver bullet pill which can kill any tumor cell while leaving healthy cells alone.
Rather than finding a single cure for cancer, it’s likely we’re going to find ourselves engineering a consistently reliable way to kill cancer. This methodology would be adjustable, scalable, and a safe way to kill tagret cells across different types of cancer.
One of the best contenders for this kind of effective cancer treatment is CAR-T cell therapy. This system takes your body’s specially-trained immune cells: T-Cells, and engineers them to fight cancer as if it was an active infection! You can read a more detailed explanation of what CAR-T Cell therapy is in my first article of this series.
Although CAR-T Cell Therapy has incredible potential for killing tumors, it’s got some huge barriers to deal with before becoming our go-to treatment for all kinds of other cancers…
Effective but Niche
As of writing this article, there are currently 2 FDA-approved CAR-T Cell therapeutics on the market right now: Yescarta for B-Cell Acute Lymphoid Leukemia and Kymriah for B-Cell Lymphoma. Against chemotherapy-resistant or relapsed leukemia and lymphoma, CAR-T fully kills tumors 80%-83% of the time without any further relapse.
All this makes CAR-T seem really promising given its potency. However, strength alone does not a good treatment make. Besides being incredibly expensive at $300k-$500k USD per patient, these CAR-T cell therapies are lacking in one really key area.
The Missing 80%
CAR-T cells are designed to deal with cancers which stem from the body’s white blood cells. These select few groups of cancers are called “Hematological malignancies”. Although it’s key that we have an effective method for treating patients with these cancers, hematological cancers only make up 20% of all cases of cancer.
The missing 80% comes from the nasty killers, solid tumors. (Ex: Breast cancer, Lung cancer, Brain cancer)
As the scientific community and pharmaceutical industry are presented with the challenge to develop more effective CAR-T cell therapies for hematological cancers, the trillion-dollar question naturally becomes:
How do we bring CAR-T to target the solid tumors? How do we treat the missing 80% of cancer patients safely, affordably, and effectively?
Teams of immunotherapists decided to experiment and find out the answer to this question for themselves.
What they’re finding out is that compared to taking down hematological cancers, treating solid tumors with CAR-T is hard and really risky. Some solid-tumor patients died when being tested with CAR-T, while other “safer” CAR-T cell therapies failed to do anything really meaningful for their patients' health.
So what’s going wrong? What’s in the way between us and getting our effective cancer killer to the other 80% of cancer patients?
The answer is: a lot of things.
What’s Stopping Us?
To understand why we got so far with blood-based cancers and struggle so much with solid tumors, we need to know how these two types of cancer differ and how T-Cells work.
Tumors are “Walled Cities”
Solid tumors are complicated places with a lot going on. Just like healthy tissue: you’ve got immune cells, fibroblasts, blood vessels and all kinds of proteins like cytokines floating around.
The complex environment of all these players in the tumor tissue is collectively referred to as the tumor microenvironment (TME). We can imagine solid tumors and their TME like a bustling city that's gone rogue.
Sending in CAR-T cells to solid tumors and their microenvironment would be like a group of 10 policemen trying to take down a group of criminals in a rogue walled city.
The Walled City is simply too complex and massive for them to handle. There’s too much happening, and the policemen are unwelcomed guests in an area trying to stop them.
You can imagine our CAR-T Cells in the same way as the police squad, all while tumor microenvironments pose themselves as a complicated and dangerous “Walled City”.
Killing tumor cells with the TME as an obstacle, our CAR-T cells begin to struggle hard. They specifically fall short in:
- Navigating to and finding the tumor (Migration)
- Surviving and proliferating in the Tumor Microenvironment
- Staying functional (T-Cell Exhaustion)
All of these problems with these T-cells reduce how effective our CAR-T treatments are for solid tumors.
Antigens and Confusion
Solid tumors are naturally built to be harder for our CAR-T cells to do their cancer-killing job. T-Cells normally take input on special “T-Cell Receptors” on their cell surface to identify and kill their target pathogen.
These receptors detect and bind to antigens, which are molecules that indicate the presence of a specific pathogen in your body. They basically act like a suspect’s fingerprint when pursuing a criminal.
Your average CAR-T cell would have one receptor per cell, designed to find and kill a specific type of tumor cell with a target cancer antigen on it.
This model works well for blood-based cancers where each cancer will have a select few antigens that are purely associated with that type of cancer, nothing else. The CAR-T cell cops have clear fingerprints that can vindicate their suspects easily.
Solid tumors are a completely different story, where each cancer type will have diverse sets of antigens which can also be expressed by healthy parts of your body.
This is like the police having smudged fingerprints of 1000 people in the walled city and not being able to the distinct criminals from the ordinary residents. You’re very likely going to end up arresting the wrong people if you send in your police officers.
When translating this to CAR-T cell therapies, it means that CAR-T cells that are put in a solid tumor patient can mistakenly spot their target antigen in a healthy area of the body. This has lead to cases of CAR-T cells attacking their patient’s own healthy tissue killing them.
In the instances where CAR-T does successfully kill off most of the tumor cells with a specific antigen, we also sometimes get antigen escape. This happens when a tumor cell quickly evolves to express a different antigen that doesn’t get it picked up by hunting CAR-T cells. This tumor cell criminal is essentially putting on fake fingerprints to escape our police CAR-T Cells.
“Solid Solutions for Solid Tumors”
You may have a grim picture in your head now when it comes to potentially curing solid tumors. How on Earth can our engineered CAR-T cells kill these complicated and monstrous solid tumors?
Better Navigation, Better Survival
For our CAR-T Cells to navigate the monstrous size and complexity of solid tumor microenvironments, they’re going to need serious backup. For this, we can call upon the help of special signaling proteins called chemokines. These proteins help navigate immune cells to their targets by signaling themselves as attractive chemical beacons, like a carrot on a stick for your CAR-T cell.
When injected alongside immunotherapy, the right chemokines will help T-Cells navigate their way to the tumor site. These chemokines also help trigger a helpful amount of inflammation around the tumor.
We have already seen success with chemokines helping the treatment of skin cancer (Melanoma), where CAR-T cells that were combined with chemokines CXCR1/CXCR2 had much more success when navigating the Tumor Microenvironment.
Alternatives to chemokines for helping with navigation also exist. Another option we have is a special kind of T-Cell called tumor-infiltrating lymphocytes, which are less common T-cell populations that specialize in fighting tumor cells. When we engineer Tumor-infiltrating lymphocytes specifically, we can get an even more targetted T-Cell treatment for cancer!
In the end, navigating the tumor microenvironment is key for adapting CAR-T treatments to solid tumors. If our CAR-T policemen can’t navigate the complex nooks and crannies of the tumor “walled city” microenvironment, there will be little-to-no hope of us catching the criminal tumor cells we’re hunting for!
Avoiding T-Cell Exhaustion
One of the most notable ways that CAR-T falls short in the solid tumor environment is through T-Cell Exhaustion, a state where T-cells stop functioning in any meaningful way for the immune response.
We see a lot of T-cell exhaustion with CAR-T cell experiments in solid human tumors, and there are reasons why:
- Being in the tumor microenvironment speeds up the process of T-Cell exhaustion.
- The current standard CAR-T cell engineering processes speed up the progress to T-cell exhaustion in CAR-T cells.
- We genetically modify T-cells to grow their CARs in random places on the T-Cell genome- this helps speed up T-cell exhaustion progress too.
- Certain types of T-Cells are just better fit to survive and proliferate in the tumor microenvironment.
Making critical changes in the way we select and engineer CAR-T cells is hypothesized to help solve many of these factors that contribute to T-cell exhaustion in CAR-T therapies.
We’re already seeing progress with changing the approach to CAR-T cell genetic engineering. When scientists introduced a CAR gene into the TRAC region of a T-Cell genome, they ended up creating a CAR-T cell which had noticeably fewer issues with T-Cell exhaustion!
Just by changing a few small steps in the way we build this cancer therapy of the future, and we’re well on our way to beating solid tumors.
Checkpoint Inhibitors: Killing the loopholes
It turns out that the struggles don’t end there for our CAR-T cells in solid tumors. Tumor cells themselves are infamous for capitalizing off special brakes that our T cells have designed into them.
These immune cell brakes are also known as immune checkpoints, and they are often used in cancer to stop an immune cell from killing a tumor cell. What legal loopholes can do to protect certain criminals from the law, immune checkpoints do for tumor cells.
These immune checkpoints have proven themselves to be a big part of why we can’t get CAR-T cell therapies working reliably in solid tumors. So long as cancer keeps exploiting these T-cell brakes, curing solid tumors with CAR-T is not feasible.
We cab combat the checkpoints with our own trump card- immune checkpoint inhibitors.
In this picture, PD-1 and PD-L1 are T-cell checkpoint inhibitors in cancer. Once they bind, the T-Cell cannot kill a tumor cell.
Afterward Anti PD-1 and Anti PD-L1 checkpoint inhibitors block PD-1/PD-L1 binding, allowing the T-Cell to continue killing the tumor cell.
By blocking off the various loopholes that cancer has evolved to take advantage of in our immune system, we give our immune cells the critical upper hand it needs to beat back solid tumors!
Final Thoughts + Key Takeaways
The emergence of CAR-T cells marked one of the most powerful anti-cancer therapies in our toolbox to date. As of now, a few problems still stand in the way between our CAR-T cells and being able to treat solid tumors.
The challenges this “walled” tumor city poses to our CAR-T cells are:
- Navigating CAR-T cells to solid tumors in the body (Migration)
- Surviving and proliferating in the solid tumor microenvironment
- Antigen Specificity (CAR Design)
- T-Cell Exhaustion
The cure for cancer will not be a “silver bullet” pill which kills all tumor cells. Likewise, there will not be a single cool add-on to CAR-T cell therapy that suddenly allows us to kill all the solid tumors out there.
However, all of this really outlines the magic one-up that CAR-T has on chemotherapy drugs- adjustability. Looking at all these diverse tools, the way to curing solid tumors will likely lie in how we adjust our CAR-T therapies and what tools we combine CAR-T with for future cancer treatment plans!
Once we get the right tools and combinations for CAR-T treatments, having cancer should undergo a transformation in meaning.
For patients, cancer today is a long and drawn-out battle of suffering, with the added fear of potential relapse. Cancer tomorrow should be a minimally painful and swift therapy, without any worry of cancer potentially relapsing.
While we figure out how to optimize these tools and combinations, the scientific and medical communities need to deal with one final little problem with CAR-T cell therapy: the cost.
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Sources and Reading
Tumor Microenvironment, and Mitigation Strategies
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