Supernatural T cells: genetic modification of T cells for cancer therapy

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Abstract
Despite having the power to protect us against infectious diseases, the immune system that Mother Nature provides ultimately fails when it comes to cancer. The same immune-system checks and balances that guard against autoimmunity lead to fundamental shortfalls and deficiencies in the antitumour capabilities of the endogenous immune system. Our understanding of the molecular events that are important in the recognition of microorganisms by immune cells, and the downstream signalling processes that are important in mediating a response to these microbial threats, has led to the design of genes that can enable us to correct deficiencies in the anticancer immune response. The endogenous immune system often lacks effective tumour-specific T cells, but specificity can be provided by genetic modification of 'ordinary' T cells with genes that encode cell-surface receptors that allow recognition of tumour cells. Examples of such receptors are T-cell receptors from rare responding patients or chimeric receptors that incorporate tumour-specific monoclonal antibodies. It is possible to combine, within a single chimeric-receptor gene, molecular domains from several signal-transducing molecules to produce a 'super receptor' that endows T cells with increased antitumour activity. When engaged in the struggle with tumour cells, natural T cells quickly 'tire', leading to their exhaustion or death. Various genetic strategies can be used to extend the lifespan of tumour-reactive T cells, with the possibility of producing the ultimate 'immortal' tumour-fighting cellular warriors. Tumours might lack appropriate molecular signals that are important for attracting endogenous tumour-specific T cells. Genetic modification can be used to guide these T cells and enable them to home to, and penetrate, tumour tissue. Tumours can produce inhibitory factors that can dampen the immune response, but T cells can be transduced with genes that endow them with resistance to such factors, thereby allowing them to realize their full antitumour potential. With further improvements in the technology and the safety of genetic-modification strategies, it might soon be possible to transduce ordinary T cells with multiple genes to endow them with a coordinated genetic programme that gives them extraordinary activity against cancer.

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