Cell-based molecularly targeted therapy: targeting oncoproteins with T cell receptor gene therapy
Christian S. Hinrichs
Christian S. Hinrichs
Published March 12, 2018
Citation Information: J Clin Invest. 2018;128(4):1261-1263. https://doi.org/10.1172/JCI120386.
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Cell-based molecularly targeted therapy: targeting oncoproteins with T cell receptor gene therapy

Abstract

As oncogenes drive carcinogenesis and promote cancer cell survival, they are highly attractive therapeutic targets, and oncogene-targeting small molecules have achieved some clinical success. While many oncogenes are presently considered to be “druggable,” tumors often acquire treatment resistance, and patients are rarely cured in response to oncogene-specific treatment. In this issue of the JCI, Veatch and colleagues describe a patient with metastatic acral melanoma who experienced a complete tumor response following infusion of tumor-infiltrating T cells that targeted multiple tumor antigens, including a BRAFV600E driver mutation. T cells genetically engineered to express an anti-BRAFV600E T cell receptor (TCR) from the patient demonstrated recognition of an epitope that spanned the BRAFV600E mutation. These findings suggest that BRAFV600E might be targeted therapeutically with adoptive transfer of anti-BRAFV600E T cells. This research supports the emerging therapeutic paradigm of targeting oncogenic drivers with T cell immunotherapy.

Authors

Christian S. Hinrichs

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Figure 1

TCRs that recognize tumor antigen epitopes that encompass oncoprotein mutations have potential for potent immunotherapy.

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TCRs that recognize tumor antigen epitopes that encompass oncoprotein mu...
For many types of cancer, small molecule inhibitors to specific oncoproteins have not been identified or have limited efficacy due to off-target effects and acquisition of treatment resistance. In this issue, Veatch and colleagues characterized the T cell response in a patient who had a complete tumor response following infusion of tumor-infiltrating T cells that targeted multiple tumor antigens. TCRs from this patient recognized an epitope that encompassed the driver mutation within an oncoprotein. Targeting of oncoproteins with T cells, which kill tumor cells, rather than small molecules, which inhibit tumor cells, may permit the development of more effective treatments. Additionally, the highly specific oncoprotein targeting by TCRs may reduce the off-target toxicity of treatment.