Chimeric antigen receptor (CAR) T cell therapy is a type of cancer immunotherapy that utilizes engineered synthetic receptors (CARs) to redirect T cells (a type of white blood cell or lymphocyte) to recognize and eliminate the target antigen-containing cells.

Radiation therapy, chemotherapy and surgery have been the traditional options to fight cancer. However, the CAR T cell therapy approach has revolutionized the cancer treatment field with the idea of treating patients by enhancing their own immune systems.

CAR T cell therapy has proven successful as a curative treatment option for hematological cancers and has gained widespread adoption. This approach is now being tested in a wider range of cancers that have historically been difficult to treat.

This article provides a high-level understanding of CAR T cell therapy, its side effects, challenges and current research.

Understanding CAR T cell therapy

Our body has two types of blood cells, red blood cells and white blood cells. Red blood cells are tasked with carrying and delivering oxygen to every part of our body. White blood cells are considered the body’s defenders and constitute a major component of the immune system. They play a crucial role in fighting disease and infection from foreign pathogens and regulating dysfunctional non-foreign cells.

However, when it comes to cancer cells, our immune system can’t always identify these cells as distinct from normal cells. Therefore, scientists came up with an approach to engineering lymphocyte cells to make them capable of recognizing and acting against cancer cells. This approach is considered an immunotherapy and is the premise for CAR T cell therapy.

During CAR T cell therapy, blood is collected from the patient's body to isolate T cells and genetically engineer them to recognize an antigen expressed on the target cell’s surface. The target antigen differs based on the type of cancer for which the CAR T cell therapy is intended to treat. When enough CAR T cells have been produced in the lab, they are administered to the patient through an intravenous infusion. Each CAR T cell is considered the drug, and therefore great care is taken throughout the manufacturing and administration process to ensure proper cell numbers for dosing.

CARs are constructed with critical structural features that enhance their therapeutic efficacy. Some structural components include:

• Antigen-binding domain: It recognizes the target tumor antigen.
• Hinge and a transmembrane region: Link CAR intracellular and extracellular domains.
• Costimulatory domains: Influences CAR T cell cytokine secretion, T cell proliferation and in vivo antitumor activity.
• Activation domain: It kills tumor cells by facilitating the release of cytokines, activating T cells and transducing extracellular signals.

Current CAR T cell therapies

The FDA has approved several CAR T cell therapies targeting CD19 and B-cell maturation antigen (BCMA) for relapsed hematologic malignancies which reinvigorated the field.

The following CAR T cell therapies approved by the FDA are designed to treat diseases such as multiple myeloma, lymphoma and leukemia.

• Kymriah (Tisagenlecleucel) from Novartis was first approved in 2017 and is designed to treat B-cell acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (NHL).
• Yescarta (Axicabtagene ciloleucel) from Kite Pharma (Gilead) was also approved in 2017 and is designed to treat B-cell non-Hodgkin lymphoma (NHL) and follicular lymphoma.
• Tecartus (Brexucabtagene autoleucel) is another Kite Pharma (Gilead) development and was approved in 2020. It is designed to treat mantle cell lymphoma (MCL) and B-cell acute lymphoblastic leukemia (ALL).
• Breyanzi (Lisocabtagene maraleucel) from Juno Therapeutics (Bristol-Myers Squibb) was approved in 2021 and designed to treat B-cell non-Hodgkin lymphoma (NHL).
• Abecma (Idecabtagene vicleucel) from Celgene (Bristol-Myers Squibb) was approved in 2021 and designed to treat multiple myeloma.
• Carvykti (Ciltacabtegene autoleucel) from Janssen Biotech (Johnson & Johnson) was approved in 2022 and designed to treat multiple myeloma.

Challenges, limitations and side effects of CAR T cell therapies

Though CAR T cell therapy has been found to be effective, not all patients respond to the treatment in a similar way. In some cases, relapse or resistance to the treatment is also observed. Furthermore, CAR T has so far been found ineffective in treating solid tumors, such as brain and breast cancer.

Some of the identified challenges can be traced back to the CAR design or manufacturing process. It is important for CAR T cell therapy developers to consider performance characteristics and develop the proper assays for testing. These assays are a requirement for regulatory filings and include testing for things like vector copy number, identification, potency, dosing, stability, contamination and comparability (if changes to the process are made).

CAR T cell therapy is designed to act on cancer cells by targeting the antigen present on their surface. It can, however, cause unwanted toxicity and off-target effects if these antigens are expressed in normal cells and the CAR T cells act on them as if they were cancer cells. One example would be CAR T cells targeting CD19+ normal B cells.

Furthermore, some serious side effects of CAR T cell therapy are also observed in patients, such as:

• Infections
• Depletion of antibody-producing B cells (can be caused by pre-treatment immunosuppression requirements)
• Cytokine release syndromes (CRS), such as hypoxia, hypotension and even multi-organ failure
• Neurotoxicity and neurological side effects
• Allergic reaction
• Seizures
• High blood uric acid levels

In addition to the inability to currently treat solid tumor cancers, CAR T cell therapy can suffer from incomplete or non-sustained responses at 6 or 12-months leading to relapse. This can be attributed to T cell exhaustion.

Ongoing research and future developments

Considering the efficacy and approach of CAR T cell therapies, scientists are optimizing the treatment strategy to expand its application and effectiveness. Primary targets include solid tumors and expanded labeling for currently approved treatments. Advocacy for the use of CAR T cell therapies as a first line treatment is also gaining momentum based on research highlighting lower efficacy attributed to chemo and radiation.

Other than T cells, natural killer (NK) cells and macrophages are also being tested for the development of CAR therapies. Combinatory therapies such as the use of checkpoint inhibitors with CAR T cells are in clinical trials.

While all the currently approved CAR T cell therapies are autologous, further work is being focused on the development of allogeneic strategies. This would allow the field to have an off-the-shelf option for treating patients that eliminates starting material quantity and quality challenges associated with autologous therapies.

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