The immune system is one of our key defenses against cancer. Cancer cells have distinct features on their surface that allow immune cells to find and eliminate them. But they also have ways of hiding from the immune system so that they can grow and spread.
Researchers have discovered that there are ways to stimulate the immune system to overcome cancer’s clever tricks and eliminate cancer cells, an approach to treatment called immunotherapy. One way to do this is to use engineered T cells.
What is a T cell?
The immune system makes a variety of different cells that have different functions. One of these is a T cell, which the body produces in order to eliminate infections, such as a virus or bacteria, or unhealthy cells, such as cancer cells. The T cell looks for an antigen, a feature on the invader or harmful cell that acts like a signal and lets T cells know that its carrier does not belong in the body.
Once located, a protein on the T cell’s surface called a receptor attaches to the antigen. Each receptor is specific to one antigen. The attachment causes a reaction that produces molecules to eliminate the invader or harmful cell.
But in order for T cells to “see” what they need to eliminate, another type of immune cell needs to present the antigen on a part of the cell called an MHC complex. The interaction between the receptor on the T cell and MHC complex on the antigen-presenting cell activates T cells to attack.
Cancer can hijack this system in various ways:
• T cells may not be made in high enough quantities to have an effect
• T cells that are produced do not work properly or get exhausted
• Cancer cells reduce the availability of MHC, so T cells can’t find the antigens and the cancer cells
Researchers have discovered that they can treat cancer by manipulating T cells in the lab and giving them back to a person with cancer. This process, called “adoptive cell therapy,” is a way to make a T cell more effective against cancer. And, because T cells monitor the body for an antigen for years after it is first detected, a single treatment has the potential to be effective for many years – what researchers call a “living drug.”
Dr Jean-Sébastien Delisle, an immunotherapy researcher at Hôpital Maisonneuve-Rosement in Montreal, says there are many exciting developments in the field, but one aspect is the speed that clinical applications can happen. “We can bridge biology into therapies very quickly,” he says. “We can study T cell biology, modify a cell and use them in patients within a relatively short time. It’s moving very quickly.”
In this article, we discuss 3 forms of adoptive T cell therapy and engineered T cells that are progressing into clinical settings: tumour infiltrating lymphocytes (TILs), T cells with cloned T cell receptors (TCRs) and chimeric antigen receptors (CARs).
Tumour-infiltrating lymphocytes (TILs)
A tumour usually contains many different types of cells, not just cancer cells, and may even include immune cells at levels that are not harmful to the tumour. Researchers can exploit this composition of tumours to develop a way to treat them.
When a doctor takes a biopsy of a tumour, researchers can isolate the T cells inside the tumour, called tumour infiltrating lymphocytes (TILs). They look for the T cells that have the cancer-fighting properties they need, and then grow these T cells in the lab into large numbers to be re-injected back into the person they came from.
Researchers have been studying this approach for more than 30 years. In fact, a small clinical trial published in the New England Journal of Medicine in 1988 showed some success with using TILs for treating melanoma. The trial showed that tumours in 11 of 20 people with advanced melanoma shrunk after treatment with TILs. This was one of the early trials of this technique, and it caused a lot of excitement when it was first published.
Billions of cells need to be given to patients
The greatest benefit to this strategy is that researchers don’t need to change the T cells at all, but simply grow them to large numbers. However, the T cells need to be isolated from each individual undergoing the treatment and then grown, which can be expensive and time-consuming.
Dr Brad Nelson, a researcher funded by the Canadian Cancer Society (CCS) at the BC Cancer Agency in Victoria, explains that in this treatment, researchers need to grow and inject a huge number of cells – about 10 to 100 billion. “Each T cell engages with each cancer cell, similar to ‘hand-to-hand combat,’” he explains. “We want to flood the body with T cells so that they can tackle all of the cancer cells wherever they might be hiding.” It can take several weeks to a couple of months to expand the population of cells to get to this size.
Dr Nelson and his team are using a similar approach to TILs in their research with a key difference: instead of using T cells that target any antigen found on cancer cells, they find T cells that target the important genetic changes that cause cells to become cancerous. This innovative approach results in a population of T cells that are highly specific and “hit the cancer where it lives.”
In previous work, they identified T cells in the blood that target these mutations and can be used for adoptive T cell therapy in lymphoma. With their current CCS grant, Dr Nelson and his team are now finding ways to streamline the process of making huge numbers of these T cells, making it cost-effective, safe and efficient.
“This kind of work is essential before a clinical trial testing this approach can be done,” says Dr Nelson. “We’re so grateful that CCS is funding this work.”
Tumours can avoid immune response
One of the significant challenges with TILs is that tumours still have many different ways to escape immune responses, which they can use to hide from the T cells – even if T cells are present in large numbers. Dr Delisle has a CCS Innovation Grant with Dr Nathalie Labrecque to study how T cells locate, travel to and enter tumours in the context of adoptive T cell therapy.
“Some tumours are not welcoming to immune cells,” says Dr Delisle. And if T cells can’t find and enter a tumour, they aren’t able to have an effect. “If we can understand how a T cell responds to signals from a tumour and generate T cells that do this, T cells will be able to get into the tumour much better.”
While work on the project is still ongoing, the early results are encouraging. “We suspect that if we take the backbone of adoptive T cell therapies and make some changes so that they locate tumours better and are more toxic, we can probably get the results we’re seeing now with other engineered cells,” says Dr Delisle.
T cells with cloned T cell receptors (TCRs)
As genetic technology has advanced, researchers have been able to try different ways of changing T cells to be more effective than naturally occurring versions.
In one approach, researchers remove T cells from the body and look for ones that have a specific antigen receptor. They can copy, or clone, the genetic material responsible for making the receptor and insert it into T cells that don’t have it. They can then expand this population of T cells with cloned T cell receptors (TCRs) and give them back to the person the T cells came from.
Cloned TCRs can be more sensitive to cancer
Researchers can look for and clone the specific receptors that they want, and they are able to make some changes to improve the effectiveness of the receptor. As a result, they can create T cells with receptors that are more sensitive and more strongly attracted to specific antigens than naturally occurring T cells.
But they share a key feature with T cells – they still need other immune cells to present the antigen on the MHC complex in order to “see” it. This means that cancer cells still have the potential to hide from these engineered cells by blocking other cells from producing MHC.
In addition, serious side effects can occur with this treatment. Sometimes an antigen found on cancer cells can also be found in other cells, and if large numbers of T cells attack these antigens on healthy cells, serious side effects can occur. Choosing antigens that are highly specific to cancer is very important.
Clinical trials demonstrated success and challenges
Early trials of this strategy in melanoma showed that it could work for cancer treatment. Researchers tested T cells with TCRs targeting different cancer antigens found on melanoma cells. The trials were small, but between 12 and 30% of the participants responded to the treatment, enough to encourage researchers to keep exploring the approach.
Researchers saw better success in a trial focused on antigens found on synovial sarcoma and melanoma cells. In one small trial, tumours in 4 of 6 participants with synovial sarcoma and 5 of 11 participants with melanoma shrunk after treatment. Another small trial targeting an antigen in multiple myeloma found that 80% of the participants responded to the treatment.
Other trials emphasized the potential side effects that can occur when TCRs are genetically modified to generate a stronger response. In a separate trial of TCRs targeting an antigen in melanoma and synovial sarcoma, 3 of 9 participants experienced severe side effects, including damage to brain cells, even though the antigen did not seem to be present on these healthy cells before treatment. The trial showed that side effects can be unpredictable, and the approach should be used carefully. Yet, despite setbacks there is a lot of encouraging research and positive results, and clinical trials of this approach in a variety of cancers are ongoing.
CAR (Chimeric Antigen Receptor) T cells
Taking the idea of TCRs a step farther, researchers are now able to design T cells with receptors that do not come from existing T cells but are designed and synthesized in the lab. Researchers give T cells genetic material that has been engineered to produce receptors – called chimeric antigen receptors (CARs) – that do not exist in natural T cells.
“We’re really excited about the potential of CARs,” says Dr Nelson. “We’re working on the next generation, making them safer and able to target more cancers, while also finding ways they can be introduced into the Canadian health care system in a cost-effective way.”
Because CARs are synthetic, researchers can design CARs in many different ways to overcome the challenges that come with other forms of adoptive therapy. They are completely customizable and, in theory, can be designed to be highly specific to cancer cells.
An important part of CAR design is that they don’t depend on the MHC complex to see the antigen, but can attach directly to the antigen to launch an anti-cancer immune response. This key difference from T cells with cloned TCRs means that CAR T cells can find and eliminate cancer cells, even if the cancer cells reduce MHC as a defence.
Using CAR T cells in blood cancer treatment
Most of the success of CAR T cells has been seen in blood cancer, specifically leukemia and lymphoma.
Researchers have developed CARs that target a protein called CD19, which is found on most B cells. B cells are one type of white blood cell, and they are the primary type of cell affected in the most common forms of lymphoma. People can survive without B cells as long as they are treated for this deficiency, so researchers can target this antigen without worrying about the side effects that can occur with targeting other antigens found on healthy cells.
Recent clinical trials testing CAR T cells in B cell blood cancers produced exciting results. In one trial, lymphoma or leukemia was eliminated in 8 of 15 participants after only one injection of CD19-targeted CAR T cells, and in another, leukemia was eliminated in 27 of 30 participants. This success excited the research community about the potential of CARs and encouraged researchers to study CAR T cells for treating other types of cancer.
Two forms of CAR T cell treatments were approved for use in the US in 2017 (one for B cell lymphoma, one for advanced leukemia), though none have been approved in Canada yet. “This is a milestone in the history of medicine,” says Dr Nelson. “We’ve been talking about genetically modifying T cells for decades, and now it’s moving into the mainstream.”
CARs can still cause side effects
But CARs have not come without their own challenges and side effects. One side effect is known as cytokine release syndrome, which happens when large numbers of activated T cells attack tumours and the body is flooded with cytokines – the molecules that attack cancer cells. In some patients, this results in flu-like symptoms, but in others, it can be very serious and even fatal. In most cases, it is treatable, but treating it also shuts down the anti-cancer T cell activity.
Because researchers can design and customize CARs, they are working on solutions to this type of problem. They are looking at ways to include genes that act like switches to turn off T cell activity after a certain time or in the presence of toxic molecules.
Similar to TCRs, CARs may also target healthy cells that have the same antigen as a cancer cell, which can result in damage to healthy tissue. In addition to selecting antigens that are highly specific to cancer, researchers are exploring CAR T cells that require 2 antigens to be present, or perhaps requiring a cell component to be absent, as ways to make them even more specific.
Dr Nelson explains that the CARs of today are really just the first generation and can be compared to cars – as in automobiles – with no brakes or steering wheels. Adding safety features like that is just a matter of research.
“There are challenges right now, but I’m confident that all of these problems can be solved,” says Dr Nelson. “With more research, we’ll be able to develop better designs that will turn CARs into sophisticated therapeutics. With that will come increased safety and lower cost.”
CARs have not been effective for solid cancers
Despite the success of CARs in blood cancer, they haven’t been very successful in solid cancers, for example lung cancer.
Researchers haven’t yet been able to identify an antigen that is found on tumour cells in solid cancers that isn’t also found on healthy cells. And tumour cells in a solid cancer can be very different from each other, so antigens may not be found on every cell throughout a tumour. A treatment could leave behind many cancer cells that do not have the antigen, which may regrow the tumour.
Addressing these challenges is the focus of many researchers. A number of clinical trials testing CAR T cells for solid cancers are underway, including brain cancer, colon cancer and liver cancer. Researchers have already seen reason for hope, with some success in a trial of neuroblastoma, where a small trial testing a CAR T cell targeted toward an antigen on neuroblastoma cells stopped cancer growth in 3 of 11 participants. While just a small number, it is reason for optimism.
Future Directions & Conclusions
The different forms of adoptive cell therapy and engineered T cells show promise as highly effective treatments for cancer. And they all have challenges that will need to be overcome before they become more widely used.
At the core of many of these challenges is that these immunotherapies are living cells, not drugs. Drugs work on one known and well-understood mechanism, but T cells can work in different, complex ways to eliminate cancer. This can be a great strength, but it also means that they may be less predictable than drugs.
In addition, unlike drugs, these approaches are currently patient-specific. Whether using TILs, T cells with TCRs or CAR T cells, the T cells need to be taken from each individual in order to generate T cells for that person’s specific cancer antigens and to avoid immune system rejection of the cells. As a result, these treatments are very expensive and time-consuming. Future research may focus on developing “off-the-shelf” T cell therapies that could be used in multiple patients, which would reduce the costs and the time associated with these therapies.
Researchers are also studying how to use these strategies in combination with other immunotherapies to make them better. For example, combining adoptive T cell therapy with checkpoint inhibitors – a form of treatment that shuts down one of cancer’s defenses against the immune system – could be more successful than either treatment alone.
This branch of immunotherapy is still in its early days, and while there are many challenges that remain, researchers are excited about the potential for impact against cancer.
“It’s exciting. We still don’t really know where this research will go,” says Dr Delisle. “But we know that we can do it, and we just need to make it better.”