T-cell Receptors for Clinical Therapy: In Vitro Assessment of Toxicity Risk

• Published in: Clinical cancer research Vol. 23; no. 20; pp. 6012 - 6020
• Main Authors: Kunert, Andre, Obenaus, Matthias, Lamers, Cor H J, Blankenstein, Thomas, Debets, Reno
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.10.2017
• Subjects: Amino Acid Motifs; Animals; Antigens; Antigens, Neoplasm - immunology; Biomarkers, Tumor; Cancer; Cross-reactivity; Cytotoxicity Tests, Immunologic - methods; Cytotoxicity, Immunologic; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Humans; Immunotherapy, Adoptive - methods; In Vitro Techniques; Lymphocyte Activation - genetics; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Neoplasms - immunology; Neoplasms - therapy; Peptides; Protein Binding - immunology; Receptors; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Risk assessment; Side effects; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Therapy; Tissues; Toxicity; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-1012

Adoptive therapy with T-cell receptor (TCR)-engineered T cells has shown promising results in the treatment of patients with tumors, and the number of TCRs amenable for clinical testing is expanding rapidly. Notably, adoptive therapy with T cells is challenged by treatment-related side effects, which calls for cautious selection of target antigens and TCRs that goes beyond their mere ability to induce high T-cell reactivity. Here, we propose a sequence of assays to improve selection of TCRs and exemplify risk assessments of on-target as well as off-target toxicities using TCRs directed against cancer germline antigens. The proposed panel of assays covers parameters considered key to safety, such as expression of target antigen in healthy tissues, determination of a TCR's recognition motif toward its cognate peptide, and a TCR's cross-reactivity toward noncognate peptides. .