Chimeric Antigen Receptor T-cell (CAR-T) therapy for Solid Tumours

T-cells are a type of white blood cells. T-cells have the capacity to recognise abnormal cells, and then destroy these abnormal cells. Adaptive immunity—which is coordinated by B-cells and T-cells—is essential for defending the body against harmful intruders. 

Despite the unsatisfactory clinical results of early immunotherapies like interleukin (IL)-2 and interferon-gamma (IFN-γ), new immunotherapies introduced in the 21st century have produced strong clinical outcomes, making cancer immunotherapy one of the mainstays of anticancer treatments. By genetically modifying the aforementioned immune cells, adaptive immunity can be utilised to strengthen the body's defences against cancer.

CAR-T Structure and Mechanism 

Adoptive transfer of T-lymphocytes derived from autologous peripheral blood and modified to express chimeric antigen receptors (CARs) has resulted in remarkable therapeutic responses, especially in patients with hematologic malignancies.

A transmembrane domain that secures the CAR to the cell membrane, an extracellular target-binding domain, a hinge region, and one or more intracellular domains that provide activation signals are the usual components of CARs' modular design. CARs are fusion proteins that combine T-cell signalling domains with antigen-recognition domains.  Antigens can be selectively recognised by T cells that have been genetically modified to produce CARs. 

Image 1: CAR-T basic mechanism 

Who can be treated with CAR-T? 

Patients with relapsed aggressive forms of Acute Lymphoblastic Leukaemia (ALL) and relapsed non-Hodgkin lymphoma, such as diffuse large B-cell lymphoma (DLBCL), respond especially well to CAR T-cell therapy, especially if at least two previous treatment regimens have not produced the desired results.

Extending CAR-T to Solid Tumours: Challenges

Although CAR T-cell therapy has shown remarkable effectiveness in treating blood malignancies and other studies have applied the concept to other cancers, solid tumours have not yet seen the same level of response from CAR T cells.  The tumour microenvironment (TME) of solid tumours is significant and poses challenges to the homing, activation, and survival of CAR T-cells.

The TME's uneven vasculature is one of its physical features.  As tumours grow, a hypoxic situation brought on by the increasing tumour mass without corresponding nutrition delivery sets off a "on switch" for angiogenesis, which is thought to be a characteristic of cancer.  Angiogenesis initiation is frequently chronically stimulated in tumours and is also impacted by secreted substances from immune cells and surrounding malignancy.  Cell populations and metastasis can be significantly impacted by the irregular blood vessels created by chronic stimulation of angiogenesis, which frequently result in zones of high and low circulation, excessive capillary branching, and blood vessel leakage.

Image 2: Healthy cell vs Tumour cell

The TME has a wide variety of immune cell types.  While many are tumor-promoting, some are tumor-antagonizing.  When tumor-antagonizing immune cells identify damaged cancer cells, an anti-tumor response is triggered. However, the tumor's multiple immunosuppressive strategies, including metabolic alterations, angiogenesis, and immunosuppressive cytokine production, often lessen the effectiveness of anti-tumor immune cells and even drive them away from the TME. Pro-tumor immune cells, which aid in the suppression of an anti-tumor immune response, are supported by the TME.

Image 3: Tumour Microenvironment 

TME Effect on CAR-T Efficacy

Because CAR T cells may activate, multiply, and spread according to their environment and the stimuli they are exposed to, they are referred to as "living drugs."  This indicates that the previously mentioned immunosuppressive components of the TME can significantly impact CAR T cell effectiveness.  The TME can cause fatigue, restrict infiltration into the tumours, restrict homing to tumour locations, and potentially affect acquired resistance to CAR T-cell treatment.

Usually injected intravenously, CAR T cells can also be injected into the tumour, a technique that is currently being researched.  CAR T cells must thus pass via blood arteries in order to reach the tumour.  Due to limited access, the TME's inadequate vasculature hinders CAR T cell arrival in the tumour. 

Lack of oxygen and nutrients in the TME is the main factor influencing CAR T-cell depletion.  Because T cells are sensitive to their metabolic environment, research indicates that the metabolic state of the TME has a significant impact on T-cell effectiveness.  Hypoxia, nutritional competition, and acidity are immune suppressive metabolic factors that have been previously explored. These factors promote epigenetic modifications to T cells in vivo, which modify their transcriptome and, thus, dramatically degrade their anti-tumor capabilities.  The effectiveness of CAR T cells in solid tumours is probably going to be affected by the same immunosuppressive metabolic factors. High levels of antigen stimulation are produced by the dense densities of cancer cells found in tumours.  CAR T cells thus experience chronic antigen activation, influencing development of exhaustion. 

Conclusion

CAR T cells are a significant advancement in the therapy of cancer, and their clinical performance in haematological malignancies is encouraging.  However, the immunosuppressive TME caused by pro-tumor cell populations, cytokine profiles, metabolic immunosuppression, vasculature, and other factors makes solid tumors difficult for CAR T cells to penetrate.  Despite these challenges, research is being done to alter CAR T cells or combine them with other treatments to more successfully penetrate and eradicate tumours by avoiding the TME's immunosuppressive properties.

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