Chimeric antigen receptor (CAR) T cell therapies have yielded transformative clinical successes for patients with blood tumors, but their full potential remains to be unleashed against solid tumors. One challenge is findingselectivetargets, which we define intuitively to be cell surface proteins that are expressed widely by cancer cells but minimally by healthy cells in the tumor microenvironment and other normal tissues. Analyzing patient tumor single-cell transcriptomics data, we first defined and quantified selectivity and safety scores of existing CAR targets for indications in which they are in clinical trials or approved. We then sought new candidate cell surface CAR targets that have better selectivity and safety scores than those currently being tested. Remarkably, in almost all cancer types, we could not find such better targets, testifying to the near optimality of the current target space. However, in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSC), for which there is currently a dearth of existing CAR targets, we identified a total of twenty candidate novel CAR targets, five of which have both superior selectivity and safety scores. These newly identified cell surface targets lay a basis for future investigations that may lead to better CAR treatments in HNSC.
嵌合抗原受体（CAR）T细胞疗法在血液肿瘤治疗领域已取得突破性临床成果，但其在实体瘤治疗中的潜力尚未完全释放。关键挑战在于寻找选择性靶点，我们将其直观定义为在肿瘤细胞中广泛表达、而在肿瘤微环境及其他正常组织的健康细胞中极少表达的细胞表面蛋白。通过分析患者肿瘤单细胞转录组数据，我们首先对现有CAR靶点在临床试验或获批适应症中的选择性与安全性评分进行了定义与量化。随后，我们探索了比现有测试靶点具有更优选择性与安全性评分的新型候选细胞表面CAR靶点。值得注意的是，在几乎所有癌症类型中，我们未能发现更优靶点，这证实了当前靶点空间已接近最优状态。然而，在目前缺乏有效CAR靶点的人乳头瘤病毒（HPV）阴性头颈部鳞状细胞癌（HNSC）中，我们共鉴定出20个新型候选CAR靶点，其中5个靶点同时具备更优的选择性与安全性评分。这些新发现的细胞表面靶点为未来研究奠定了基础，有望推动HNSC领域CAR疗法的优化发展。
肿瘤(癌症)患者之家