To better understand how to optimally select which TCRs to use for adoptive cell therapy, Spear et al. examined the contributions of TCR affinity, CD8 co-receptor dependence, antigen density, and TCR density to T cell functional readouts. Importantly, TCR affinity was not the best predictor of IFNγ release or degranulation, and the other factors such as antigen or TCR density are equally or more relevant.
T-cell receptor (TCR)-pMHC affinity has been generally accepted to be the most important factor dictating antigen recognition in gene-modified T-cells. As such, there is great interest in optimizing TCR-based immunotherapies by enhancing TCR affinity to augment the therapeutic benefit of TCR gene-modified T-cells in cancer patients. However, recent clinical trials using affinity-enhanced TCRs in adoptive cell transfer (ACT) have observed unintended and serious adverse events, including death, attributed to unpredicted off-tumor or off-target cross-reactivity. It is critical to re-evaluate the importance of other biophysical, structural, or cellular factors that drive the reactivity of TCR gene-modified T-cells. Using a model for altered antigen recognition, we determined how TCR-pMHC affinity influenced the reactivity of hepatitis C virus (HCV) TCR gene-modified T-cells against a panel of naturally occurring HCV peptides and HCV-expressing tumor targets. The impact of other factors, such as TCR-pMHC stabilization and signaling contributions by the CD8 co-receptor, as well as antigen and TCR density were also evaluated. We found that changes in TCR-pMHC affinity did not always predict or dictate IFNgamma release or degranulation by TCR gene-modified T-cells, suggesting that less emphasis might need to be placed on TCR-pMHC affinity as a means of predicting or augmenting the therapeutic potential of TCR gene-modified T-cells used in ACT. A more complete understanding of antigen recognition by gene-modified T-cells and a more rational approach to improve the design and implementation of novel TCR-based immunotherapies is necessary to enhance efficacy and maximize safety in patients.
Author Info: (1) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA. tspear@luc.edu. (2) Department
Author Info: (1) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA. tspear@luc.edu. (2) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA. (3) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA. (4) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA. (5) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA. (6) Flow Cytometry Core Facility, Office of Research Services, Loyola University Chicago, Maywood, IL, 60153, USA. (7) Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, 29415, USA. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29415, USA. (8) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA. (9) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA. (10) Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA.
