Identification of a Titin-Derived HLA-A1–Presented Peptide as a Cross-Reactive Target for Engineered MAGE A3–Directed T Cells

By Brian J. Cameron, A. Gerry, J. Dukes, Jane V. Harper, Vivekanandan Kannan, F. Bianchi, F. Grand, J. E. Brewer, Minnal Gupta, G. Plesa and 20 more. Science Translational Medicine, 2013

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T cells engineered to express affinity-enhanced TCRs directed to a MAGE A3 peptide cross-react with a similar, but unrelated, self-peptide. Cross-Reactive Adoptive Therapy Engineering T cells with enhanced affinity to cancer targets is a promising therapy. However, one key bottleneck in this strategy is the identification of targets that are expressed on cancer cells but not on normal healthy tissue. One way to identify these antigens is by looking at the family of cancer-testis antigens, which have restricted expression in normal tissue but are frequently up-regulated in tumors. Cameron et al. now report that a T cell engineered to target one such antigen—MAGE A3—cross-reacts with a peptide from a muscle protein, Titin. The authors developed a T cell that targeted a MAGE A3 antigen for use in adoptive immunotherapy. Although extensive preclinical investigations demonstrated no off-target antigen recognition, patients who received these T cells had serious adverse events, including fatal cardiac toxicity. The authors then used amino acid scanning to search for potential cross-reactivity of these T cells with an off-target peptide and identified a peptide derived from the muscle protein Titin. Because affinity-enhanced T cells are highly potent, this cross-reactivity was likely the cause of the off-target toxicity. This study highlights methods that may be used to prevent cross-reactivity in future trials of adoptive immunotherapy. MAGE A3, which belongs to the family of cancer-testis antigens, is an attractive target for adoptive therapy given its reactivation in various tumors and limited expression in normal tissues. We developed an affinity-enhanced T cell receptor (TCR) directed to a human leukocyte antigen (HLA)–A*01–restricted MAGE A3 antigen (EVDPIGHLY) for use in adoptive therapy. Extensive preclinical investigations revealed no off-target antigen recognition concerns; nonetheless, administration to patients of T cells expressing the affinity-enhanced MAGE A3 TCR resulted in a serious adverse event (SAE) and fatal toxicity against cardiac tissue. We present a description of the preclinical in vitro functional analysis of the MAGE A3 TCR, which failed to reveal any evidence of off-target activity, and a full analysis of the post-SAE in vitro investigations, which reveal cross-recognition of an off-target peptide. Using an amino acid scanning approach, a peptide from the muscle protein Titin (ESDPIVAQY) was identified as an alternative target for the MAGE A3 TCR and the most likely cause of in vivo toxicity. These results demonstrate that affinity-enhanced TCRs have considerable effector functions in vivo and highlight the potential safety concerns for TCR-engineered T cells. Strategies such as peptide scanning and the use of more complex cell cultures are recommended in preclinical studies to mitigate the risk of off-target toxicity in future clinical investigations.

Subfields: Genetics, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/ab5afe4da3d5916e24d989f594eace3b592151f8

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