METHODS: We isolated antigen-specific TCRs (asTCRs) from a naive library constructed with TCRs obtained from enriched cytotoxic T lymphocytes. The robustness of our asTCRs and their TCR-T cell derivatives, Tranilast (TRPV2 inhibitor), and their bivalent treatment were evaluated with prospective cross-reactive human-peptide variants and tumor cells.
RESULTS: Our study demonstrated that our naive unenhanced asTCRs and their TCR-Ts perpetuated their cognate HLA-A*02:01/NY-ESO-1(157-165) specificity, killing varying EC cells with higher cytotoxicity compared to the known affinity-enhanced TCR (TCRe) and its wild-type (TCR0) which targets the same NY-ESO-1 antigen. Furthermore, the TCR-Ts and Tranilast bivalent treatment showed superior EC killing compared to any of their monovalent treatments of either TCR-T or Tranilast.
CONCLUSIONS: Our findings suggest that dual-targeted immunotherapy may have a superior antitumor effect. Our study presents a technique to evolve novel, robust, timely therapeutic strategies and interventions for EC and other malignancies.
方法:我们从用富集的细胞毒性T淋巴细胞获得的TCR构建的幼稚文库中分离了抗原特异性TCR(asTCR)。我们的asTCR及其TCR-T细胞衍生物的鲁棒性,曲尼司特(TRPV2抑制剂),并使用前瞻性交叉反应性人肽变体和肿瘤细胞评估了其二价治疗。
结果:我们的研究表明,我们的幼稚未增强asTCR及其TCR-Ts延续了其同源HLA-A*02:01/NY-ESO-1(157-165)特异性,与靶向相同NY-ESO-1抗原的已知亲和力增强的TCR(TCRe)及其野生型(TCR0)相比,以更高的细胞毒性杀死不同的EC细胞。此外,与TCR-T或曲尼司特的任何单价处理相比,TCR-Ts和曲尼司特二价处理显示出优异的EC杀伤作用。
结论:我们的研究结果表明,双靶向免疫治疗可能具有更好的抗肿瘤作用。我们的研究提出了一种进化新颖的技术,健壮,对EC和其他恶性肿瘤的及时治疗策略和干预措施。