Immunotherapy of cancer is a type of therapy that targets the human immune system by boosting patient's natural defenses to fight cancer, rather than targeting tumour cells directly. Chimeric antigen receptor (CAR) T-cell therapy is a promising new type of immunotherapy, where patient’s T cells are collected and genetically engineered to express a receptor that recognizes a specific antigen. The adoptive transfer of CAR T cells has demonstrated remarkable success in treating hematologic cancers. However, solid tumours have barriers that are absent in hematologic malignancies. Firstly, CAR T cells must successfully traffic from the blood into solid tumour sites. There, they must successfully infiltrate the stromal elements of solid tumours in order to elicit tumour-specific cytotoxicity. Suppressive immune cells, namely regulatory T cells, myeloid-derived suppressor cells, tumour-associated macrophages and neutrophils in tumour microenvironment hinder CAR T cell binding on targeted tumour antigens. CAR T cells can rapidly become dysfunctional also due to a hostile tumour microenvironment characterized by oxidative stress, hypoxia, nutritional depletion, and acidic pH. One of the major obstacles is also the lack of specific tumour antigens that are highly and uniformly expressed on tumour cells, which can result in ineffective therapy or in on-target off-tumour effects. Many new approaches are currently being investigated to overcome these hurdles.
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