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TCR Vs. CAR-T: What is CAR-T Cell, TCR Therapy, and What are They Used For?

November 2020

Cell Therapies

Medical research and cancer treatment strategies are constantly adapting to overcome new challenges. When more traditional methods fail to fend off certain forms of cancer, patients can turn to adoptive cell therapy as a last resort. Adoptive cell therapy involves the combination of human T cells with scientific enhancements to treat diseases the body isn’t adequately equipped to handle.

One way these cells can be modified is through the attachment of an artificial T cell receptor. T cell receptors are proteins on the outer surface of lymphocytes that recognize and bind to antigens. Antigens are unique protein identifiers that exist on the surface of pathogens and other cells. Antigens and receptors function like a lock and key, each one only linking with its specific counterpart. Two T cell therapies involve the modification of receptors for the purpose of cancer treatment: CAR T cell therapy and engineered TCR therapy. 

Chimeric Antigen Receptors (CAR)

CAR T cell therapy involves binding proteins called chimeric antigen receptors to activated T cells extracted from the patient. These receptors are artificially designed to target the naturally occurring antigens on the surface of cancer cells. This enables patients to receive treatment for cancers the body would not combat on its own.

Function

There are currently three types of FDA approved CAR T cell therapies accessible for practical use. These techniques have provided the opportunity to treat certain types of lymphoma and leukemia. Clinical trials are underway for other receptor-antigen combos. As research continues and the FDA approves more cell therapies, the scope of treatable cancers will steadily increase.

Manufacturing

The specifics of creating CAR T cells depends on the desired product, but the general process is the same. Manufacturing CAR T cells starts with the extraction and isolation of human T lymphocytes. After collection, those cells must be purified, multiplied, and activated to attack harmful substances. Once a decent population of primed cells is ready, they’re altered with small chemical messengers. These messengers will carry the desired receptors to the T cell membrane and bind to them, becoming a single unit. The end product is an army of activated T cells all targeting the desired cancer cell.

Limitations

Before research and manufacturing can reach its full potential, the rate at which T cells are collected and purified must increase. There is currently a bottleneck at the manufacturing stage of CAR T cells, meaning the labor required to develop these cells is restricting the frequency at which they can be used. It takes a large amount of time and money to safely and effectively extract enough T cells to justify the manufacturing process.

T Cell Receptor Engineering (TCR)

Like CAR T cell therapy, engineered T cell receptor therapy involves treating cancer with activated T lymphocytes from the body. Both strategies attach new receptors to the cells’ surfaces, enabling them to attack different forms of cancer. The difference between the two methods pertains to what antigens they are capable of recognizing. As mentioned above, CAR T cells bind to naturally occurring antigens on the surface of cancer cells. In engineered TCR therapy, the added receptors can only link with MHC proteins.

Function

The MHC, or major histocompatibility complex, is a series of genes responsible for coding antigens that can be recognized by the immune system. The MHC marks foreign pathogens by attaching proteins to their surface for T lymphocytes to bind to. Engineered TCR therapy equips activated T cells with specific receptors that target their complementary cancer antigens. This greatly enhances the personalization of treatment and provides a higher potential for positive outcomes for patients. 

Manufacturing

The manufacturing process for TCR therapy is virtually the same as the one for CAR T cell therapy. T lymphocytes must be collected from the patient and isolated from unwanted substances. Once purified, the sample is expanded, drastically increasing the amount of T cells. Depending on the cloned sample, the cells may need to be activated to attack cancer cells. If the cells were already activated before the population growth, the next step is to attach new receptors. These receptors are attached with the same vectors as those in CAR T cells, but they will recognize different antigens when introduced back into the bloodstream.

Limitations

Engineered TCR therapy encounters the same issues as CAR T cell therapy when it comes to the difficulties and expenses of separating cells. T cells are not typically available in the necessary numbers to carry out an adequate response to prolonged battles with cancer. When they do become available, they are harnessed for treatment, not research. Medical advancements in the field of adoptive cell therapy are constant but slow due to the inaccessibility of T cells.

CAR vs TCR

CAR T cell therapy is a form of engineered TCR therapy. While these two strategies have many common aspects, their differences dictate the purpose they serve. The main difference between CAR T cell therapy and engineered TCR therapy is the receptors programmed into the cell. As mentioned previously, CAR T cells have receptors that target naturally occurring antigens. Aside from loaning out T lymphocytes, the immune system plays no role in CAR T cell therapy. TCR therapy, on the other hand, relies on the MHC to mark cancer cells with recognizable antigens. 

Benefits

In the current stages of immunotherapy, TCR therapy is a more versatile method that can be applied to more cancers. The immune system has already marked the cancer cells with predetermined antigens, meaning the process of figuring out how to program receptors is significantly easier.

CAR T cell therapy currently treats fewer cancers — but has the potential to help with many more variations with more research. This method allows researchers to program receptors for cancers that the body does not recognize or have T cells for. Once scientists can identify the naturally occurring antigens on cancer cells, they can begin to build receptors that match them.

Between CAR T cell therapy and engineered T cell therapy, the ultimate goal is to develop treatment methods for as many cancers as possible whether the body can recognize them or not.

 T Cell Separation

This research can be made simpler by streamlining different portions of the manufacturing process. The separation of T cells requires a lot of time, and the equipment can be expensive. Traditionally, researchers have used complex machines to carry out the tedious task of sorting and purifying large volumes of lymphocytes. Innovative cell separation strategies like buoyancy activated cell sorting (BACS) are more efficient and offer a better result for a lower price. BACS use microbubbles to quickly and carefully float target cells to the top of a sample, separating them from other substances. 

Why Akadeum?

Akadeum Life Sciences has developed a red blood cell (RBC) depletion kit for isolating T cells that can destroy over 99% of RBC contamination in 10 minutes or less. By using BACS for T cell isolation, scientists studying CAR T cell therapy and TCR therapy can dedicate more time and money to other aspects of the research that are more valuable. Whether you’re a large company with boundless resources or an independent researcher paying out of pocket, Akadeum has products to help you succeed.

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