T cell therapy in mice and men

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Science Translational Medicine  08 Apr 2015:
Vol. 7, Issue 282, pp. 282ec59
DOI: 10.1126/scitranslmed.aab0845

An emerging strategy for cancer immunotherapy involves genetic manipulations that program tumor-killing capabilities into patient or donor T cells. For example, lymphocytes can be engineered to express T cell receptors (TCRs) that are specific for particular tumor antigens. However, therapeutically useful TCRs are not common because tumors are derived from normal tissue, so the potential targets for TCRs are mostly self-antigens. During normal development, only T cells that bind weakly to self-antigens are allowed to survive; those that bind strongly are eliminated because they would otherwise mount an autoimmune response. Thus, the availability of T cells expressing TCRs that can bind tumor antigens with high affinity is naturally limited.

To circumvent this problem, Obenaus et al. recently developed a new strategy for generating T cells that can recognize tumors the same way they recognize viral or bacterial antigens. First, they transgenically transferred the genetic information for a repertoire of human TCRs into mice, thus developing an arsenal of T cells expressing human receptors. When human cancer antigens are subsequently inoculated into these mice, they are of course perceived as foreign and induce reactive T cells. DNA encoding the resulting high-affinity TCRs could potentially be transferred into human T cells for adoptive therapy. In fact, the research team established that TCRs derived from such mice were effective in an animal model of fibrosarcoma.

Clinical studies will be needed to establish the therapeutic value and safety of mouse-derived TCRs, since high-affinity receptors usually elicit autoimmunity. However, if these receptors are confirmed to be safe, this approach could not only increase the effectiveness of adoptive T cell therapy, but substantially speed up the development of libraries of TCRs that recognize a wide range of cancer types.

M. Obenaus et al., Identification of human T-cell receptors with optimal affinity to cancer antigens using antigen-negative humanized mice. Nat. Biotechnol. 10.1038/nbt.3147 (2015). [Full Text]

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