Adoptive immunotherapy for cancer: harnessing the T cell response

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Abstract
Populations of T cells that are specific for tumour-associated antigens can be expanded to generate large numbers of cells and transferred into tumour-bearing hosts, a process known as adoptive cell transfer (ACT)-based immunotherapy. T cells can be genetically engineered to express αβ T cell receptors (which recognize MHC-restricted peptide antigens) or chimeric antigen receptors, which are antibody-like structures capable of recognizing structures on the surface of tumour cells or tumour-associated cells. Tumours are complex masses that comprise numerous cell types, including transformed cells as well as non-transformed stromal cells and immune cells (such as myeloid cells and various T cell subsets). Transformed cells (tumour cells) express mutated genes and genes that are normally epigenetically repressed in most adult tissues, and these genes can trigger tumour masses to grow uncontrollably, resist death and invade tissues. The products of these genes can be targeted by immunotherapy. ACT can be improved by destroying host elements that interfere with the function of tumour-specific T cells. This can be accomplished using lymphodepletion mediated by chemotherapy or total-body irradiation. The differentiation state of tumour-specific T cells affects the efficacy of T cell-based immunotherapy. 'Younger', less-differentiated T cells are more effective than cells that have fully acquired effector functions. DNA sequencing might be useful in the identification of targetable neo-antigens expressed by tumours. New combinations of ACT-based immunotherapy with 'targeted therapies' offer promising new directions.