CAR T cells the future of cancer treatment

What are CAR T cells and how they work?

Chimeric antigen receptor T cells are cells that are genetically engineered (changed) in a laboratory. They have a new receptor so they can bind to cancer cells and kill them. Different types of cancer have different antigens. Each kind of CAR T cell therapy is made to fight a specific kind of cancer antigen.

Here's a breakdown of how CAR T cell therapy works:

• Collection of T Cells: The process begins by extracting T cells (a type of immune cell) from the patient's blood.
• Genetic Modification: The extracted T cells are then genetically modified in a laboratory. This involves introducing a gene that encodes a chimeric antigen receptor (CAR) into the T cells.
• CAR Structure: The CAR is a synthetic receptor that combines the antigen recognition region of an antibody with the signaling domains of T cells. This engineered receptor is designed to target a specific antigen on the surface of cancer cells.
• Expansion: The modified T cells, now expressing the CAR, are multiplied or expanded in the laboratory to create a larger population.
• Infusion: The expanded CAR T cells are then infused back into the patient's bloodstream. These modified T cells, armed with the chimeric antigen receptor, can now recognize and bind to the cancer cells expressing the targeted antigen.
• Activation and Destruction: When the CAR T cells encounter cancer cells with the targeted antigen, the CAR recognizes the antigen and activates the T cells. This activation triggers the immune system to attack and destroy the cancer cells.

CAR T cell therapy has shown remarkable success in treating certain types of blood cancers, such as certain forms of leukemia and lymphoma.

CAR T The Discovery

CAR T cell therapy was developed through the collaborative efforts of researchers in the field of immunology and cancer therapy. The foundational work that led to the development of CAR T cells can be traced back to several key scientists.

One of the pioneers in this field is Dr. Zelig Eshhar, an Israeli immunologist, who played a crucial role in designing the first chimeric antigen receptor. He created the concept of CARs in the late 1980s.

The concept gained further momentum with the contributions of Dr. Carl June(Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania .) and his team at the University of Pennsylvania. In the early 2000s, they conducted groundbreaking research, demonstrating the effectiveness of CAR T cells in targeting and killing cancer cells. Their work laid the groundwork for the first successful clinical trials.

The first clinical trial using CAR T cells to treat patients with advanced-stage chronic lymphocytic leukemia (CLL) was conducted by Dr. June and his colleagues in 2010. The trial demonstrated promising results and marked a significant milestone in the development of CAR T cell therapy.

The field has since expanded rapidly, with multiple pharmaceutical companies and research institutions contributing to the development and refinement of CAR T cell therapies. The U.S. Food and Drug Administration (FDA) approved the first CAR T cell therapy, Kymriah (developed by Novartis), in 2017 for the treatment of certain pediatric and young adult patients with acute lymphoblastic leukemia (ALL).

The Design and Structure of CAR-T Cells

T cells genetically engineered to carry synthetic CAR bind specifically targeted tumor antigens and kill these targeted tumor cells. CAR are synthetic receptors composed of an antigen-binding domain/hinge motif, transmembrane domain, and intracellular signaling domain. The extracellular antigen-binding domain, composed of a single-chain variable fragment (scFv), recognizes targeted tumor-associated antigens (TAAs) and triggers downstream signaling. The hinge/spacer region provides flexibility to allow the antigen-binding domain to access the targeted antigen. The hinge/spacer region can be adjusted to its optimal length to provide a sufficient distance between CAR-T cells and targeted tumor cells.

To improve the efficacy and safety of CAR-T cell therapy, CAR-T cells have undergone several progressive changes by modifying the CAR structure based on its intracellular signaling domains. The first generation of CAR, containing the antigen recognition extracellular signaling endodomain, displayed less efficient T cell activation and a short survival time in vivo.?

To improve the persistence and efficacy of CAR-T cells, second-generation CARs contain an additional costimulatory molecule (e.g., CD28, etc) that enhances T cell proliferation, prolongs T cell survival time, and improves clinical outcomes.?

The design of the third generation of CAR included CD3ζ and two costimulatory molecules that further enhance CAR-T cell function. The most commonly used third-generation costimulatory molecules are CD27, CD28, 41BB, ICOS, and OX-40.?

The design of fourth-generation CAR-T cells introduced T cells redirected for universal cytokine-mediated killing containing nuclear factor of activated T cells. These fourth-generation CAR-T cells can produce pro-inflammatory cytokines (interleukin [IL]-12, IL-13, and GM-CSF) upon activation and enhance the penetration ability of T cells to overcome the immunosuppressive effect of the hostile tumor microenvironment (TME).?

The fifth generation of CAR includes an IL-2Rβ fragment that induces JAK production and activates signal transducer and activator of transcription ?

Primary uses of CAR

CAR T cell therapy is primarily used in the treatment of certain types of cancer, particularly hematologic malignancies (cancers affecting the blood and lymphatic system). The primary uses of CAR T cell therapy include:

B-Cell Acute Lymphoblastic Leukemia (B-ALL): CAR T cell therapy has shown remarkable success in the treatment of B-cell acute lymphoblastic leukemia, especially in pediatric and young adult patients. The therapy has been used when other treatments, such as chemotherapy, have not been effective or have resulted in relapse.

Diffuse Large B-Cell Lymphoma (DLBCL): CAR T cell therapy has been approved for the treatment of certain patients with relapsed or refractory diffuse large B-cell lymphoma, a common type of non-Hodgkin lymphoma.

Follicular Lymphoma: In some cases, CAR T cell therapy is being investigated for the treatment of follicular lymphoma, another type of non-Hodgkin lymphoma.

Mantle Cell Lymphoma: CAR T cell therapy is also being explored for the treatment of mantle cell lymphoma, a type of B-cell lymphoma.

Difficulties in the application of CAR to solid tumors

Tumor Heterogeneity: Solid tumors are often characterized by significant heterogeneity, meaning that different regions of the tumor may express different antigens. CAR T cells are designed to target specific antigens, and the presence of multiple antigens within a tumor can make it challenging to ensure that CAR T cells effectively target all cancer cells.

Tumor Microenvironment: The microenvironment surrounding solid tumors can be immunosuppressive, containing various factors that hinder the function of immune cells, including CAR T cells. Factors such as low oxygen levels, inhibitory molecules, and the presence of immune-suppressive cells can limit the activity and persistence of CAR T cells within the tumor.

Access to Tumor Sites: Solid tumors may be located in anatomically challenging or inaccessible sites, making it difficult for CAR T cells to reach and penetrate the tumor mass. Tumor architecture, including dense stromal tissues, can create physical barriers that impede the infiltration of CAR T cells.

On-Target, Off-Tumor Effects: CAR T cells are designed to target specific antigens expressed on cancer cells. However, some of these antigens may also be present on normal tissues, leading to potential "on-target, off-tumor" toxicities. This can result in unintended damage to healthy cells expressing the targeted antigen.

Antigen Escape: Solid tumors can undergo antigen escape, where they downregulate or lose the targeted antigen, making them resistant to CAR T cell recognition. This can lead to treatment failure and disease relapse.

Safety Concerns: The potential for severe side effects, such as cytokine release syndrome and neurotoxicity, poses safety concerns, especially when treating solid tumors. Managing these side effects while maintaining therapeutic efficacy is a complex task.

Researchers and clinicians are actively addressing these challenges through ongoing studies and clinical trials. Strategies to enhance the effectiveness of CAR T cell therapy in solid tumors include combining CAR T cells with other therapeutic modalities, improving the design of CAR constructs, and developing strategies to overcome the immunosuppressive tumor microenvironment. Despite the obstacles, progress is being made, and CAR T cell therapy for solid tumors remains an area of active research and development in the field of cancer immunotherapy.

References

https://www.frontiersin.org/articles/10.3389/fimmu.2022.903562/full