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Sleuthing for toxicity

Immunocore Ltd., Adaptimmune Ltd. and University of Pennsylvania researchers have determined that off-target toxicity most likely caused the two fatalities in a cancer trial of affinity-enhanced T cell receptors.1 The results highlight the need in the cancer immunotherapy space for harnessing biologically appropriate cellular testing and deep molecular analysis approaches to minimize cross-reactivity-related toxicity in future adoptive immunotherapy trials.

A primary challenge in engineering T cells for adoptive immunotherapy is selecting a cancer-associated antigen that is absent on healthy tissues and lacks homology to other self-proteins.

Over the last few years, melanoma-associated antigen A3 (MAGEA3) emerged as one of the most promising targets for adoptive immunotherapy because it is highly expressed in a number of tumors and its expression in healthy individuals is limited to the testes.2,3

Because the human immune system has evolved to avoid the generation of high-affinity T cell receptors (TCRs) against self-proteins to preclude autoimmune reactions, endogenous TCRs must be optimized for cancer antigen affinity. On the other hand, engineering TCRs with enhanced affinity for specific tumor antigens presents the challenge of minimizing affinity for other homologous self-proteins to prevent nonspecific binding of the TCRs.

Between 2008 and 2010, an Immunocore, Adaptimmune and UPenn team led by Carl June

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