Gene-engineered T cells for cancer therapy

Key Points The abilities of T cells to coordinate immunity and to deliver lethal hits against diseased cells can be directed towards tumours by genetically modifying T cells. Genes encoding specific antigen receptors can be inserted into T cells to enable them to recognize and respond to cancer cells. Migration of T cells towards tumours can be facilitated by the expression of specific chemokine receptors in T cells. Genetic modification of T cells can enhance their proliferation and survival, leading to a sustained attack on tumours. Resistance to tumour-derived immunosuppressive factors can be provided genetically to T cells so that they can maintain their activity in a hostile environment. Genes that confer sensitivity to drugs can be used to enable the elimination of T cells if they exert toxicity against vital normal tissues. Adoptive T cell therapy using engineered T cells to improve antitumour responses is showing promise for the treatment of haematological malignancies in particular. This Review discusses the strategies to engineer T cells and the progress that has been made with using gene-modified T cells to treat cancer patients. T cells have the capacity to eradicate diseased cells, but tumours present considerable challenges that render T cells ineffectual. Cancer cells often make themselves almost 'invisible' to the immune system, and they sculpt a microenvironment that suppresses T cell activity, survival and migration. Genetic engineering of T cells can be used therapeutically to overcome these challenges. T cells can be taken from the blood of cancer patients and then modified with genes encoding receptors that recognize cancer-specific antigens. Additional genes can be used to enable resistance to immunosuppression, to extend survival and to facilitate the penetration of engineered T cells into tumours. Using genetic modification, highly active, self-propagating 'slayers' of cancer cells can be generated.