Spear Timothy T, Wang Yuan, Foley Kendra C, Murray David C, Scurti Gina M, Simms Patricia E, Garrett-Mayer Elizabeth, Hellman Lance M, Baker Brian M, Nishimura Michael I
Department of Surgery, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 S. 1st Ave, Bldg 112, Room 308, Maywood, IL, 60153, USA.
Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA.
Cancer Immunol Immunother. 2017 Nov;66(11):1411-1424. doi: 10.1007/s00262-017-2032-9. Epub 2017 Jun 20.
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 IFNγ 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.
T细胞受体（TCR）-肽段-MHC亲和力通常被认为是决定基因修饰T细胞中抗原识别的最重要因素。因此，人们对通过增强TCR亲和力来优化基于TCR的免疫疗法非常感兴趣，以增强TCR基因修饰T细胞在癌症患者中的治疗效果。然而，最近在过继性细胞转移（ACT）中使用亲和力增强的TCR的临床试验观察到了意外的严重不良事件，包括死亡，这些事件归因于不可预测的肿瘤外或脱靶交叉反应性。重新评估驱动TCR基因修饰T细胞反应性的其他生物物理、结构或细胞因素的重要性至关重要。我们使用一个改变抗原识别的模型，确定了TCR-pMHC亲和力如何影响丙型肝炎病毒（HCV）TCR基因修饰T细胞对一组天然存在的HCV肽和表达HCV的肿瘤靶标的反应性。还评估了其他因素的影响，如TCR-pMHC稳定性和CD8共受体的信号贡献，以及抗原和TCR密度。我们发现，TCR-pMHC亲和力的变化并不总是能预测或决定TCR基因修饰T细胞释放IFNγ或脱颗粒，这表明在预测或增强ACT中使用的TCR基因修饰T细胞的治疗潜力时，可能需要减少对TCR-pMHC亲和力的重视。为了提高疗效并使患者的安全性最大化，有必要更全面地了解基因修饰T细胞的抗原识别，并采用更合理的方法来改进新型基于TCR的免疫疗法的设计和实施。
