Use of tumour-responsive T cells as cancer treatment

Abstract

The stimulation of a tumour-specific T-cell response has several theoretical advantages over other forms of cancer treatment. First, T cells can home in to antigen-expressing tumour deposits no matter where they are located in the body-even in deep tissue beds. Additionally, T cells can continue to proliferate in response to immunogenic proteins expressed in cancer until all the tumour cells are eradicated. Finally, immunological memory can be generated, allowing for eradication of antigen-bearing tumours if they reoccur. We will highlight two direct methods of stimulating tumour-specific T-cell immunity: active immunisation with cancer vaccines and infusion of competent T cells via adoptive T-cell treatment. Preclinical and clinical studies have shown that modulation of the tumour microenvironment to support the immune response is as important as stimulation of the most appropriate effector T cells. The future of T-cell immunity stimulation to treat cancer will need combination approaches focused on both the tumour and the T cell.

Figure 1. Tumour vaccine cells genetically modified to produce danger stimuli (similar to granulocyte-macrophage colony-stimulating factor) to attract and mature antigen-presenting cells

Tumour-associated antigens are shed from dying vaccine cells to provide a source of antigen. Antigens can then be taken up by antigen-presenting cells, expressing co-stimulatory molecules such as B7-1, to be processed and presented to T cells. Phenotypes of CD4+ T cells can either enhance (eg, Th1) or inhibit (eg, Treg) the immune response.

Figure 2. Isolation and ex-vivo stimulation of antigen-specific tumour-reactive T lymphocytes for adoptive transfer

Autologous lymphocytes are stimulated ex vivo with antigen-loaded antigen-presenting cells, such as dendritic cells. Enriched tumour-specific T cells are then re-infused for treatment.