CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer.
Personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against metastatic ovarian cancer.
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新抗原反应性细胞毒性T淋巴细胞在精准清除癌细胞中发挥重要作用。在本研究中，我们证明了基于个性化新抗原的T细胞疗法在诱导两名负担沉重的转移性卵巢癌患者肿瘤消退方面的有效性。
我们的方法包括开发一个稳健的流程，用于体外扩增新抗原反应性T淋巴细胞。根据肿瘤的体细胞突变及其预测的HLA结合亲和力，设计并合成了新抗原肽。随后，通过与负载新抗原的树突状细胞共培养，将这些肽呈递给T淋巴细胞以进行体外扩增。细胞治疗后，两名患者的肿瘤标志物水平均显著降低，并出现明显的肿瘤消退。一名患者通过输注由新发现的新抗原生成的T细胞产品，实现了反复的癌症消退。转录组分析显示，细胞治疗后患者外周血中新抗原反应性细胞毒性淋巴细胞显著增加。这些细胞毒性T淋巴细胞表达针对新抗原的多克隆T细胞受体（TCR），并伴有丰富的细胞毒性蛋白和促炎细胞因子。新抗原靶向的疗效与免疫原性和TCR多克隆性显著相关。
值得注意的是，新抗原特异性TCR克隆型在细胞治疗后持续存在于外周血中。我们的研究结果表明，基于个性化新抗原的T细胞疗法可激发表达针对卵巢癌的多克隆TCR的细胞毒性淋巴细胞，提示其在癌症免疫治疗中具有广阔前景。
Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer.
Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression.
One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy.
These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality.
Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy.
Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
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