小柯机器人

美国费城儿童医院John M. Maris和纽约大学格罗斯曼医学院Mark Yarmarkovich团队在研究中取得进展。他们研发出靶向细胞内肿瘤蛋白的肽-CAR。相关论文于2023年11月8日发表在《自然》杂志上。

研究人员发现神经母细胞瘤免疫肽组富含肿瘤发生所必需的蛋白质肽。研究人员重点靶向了在人类白细胞抗原（HLA）-A*24:02上发现的未突变肽QYNPIRTTF，它由神经母细胞瘤依赖基因和主转录调节因子PHOX2B产生。为了靶向QYNPIRTTF，研究人员利用预测的潜在交叉反应肽，通过反平移策略开发出以肽为中心的嵌合抗原受体（PC-CARs）。研究进一步提出，当PC-CAR呈现出相似的整体分子表面时，可以识别其他HLA异型上的肽。

根据研究人员的计算建模结果，研究发现PHOX2B PC-CAR还能识别由HLA-A*23:01递呈的QYNPIRTTF，这是非洲血统人群中最常见的非A2等位基因。最后，研究人员在体外展示了对表达这些HLA的神经母细胞瘤细胞的强效特异性杀伤作用，并在小鼠体内发现肿瘤完全消退。这些数据表明，PC-CAR有可能扩大免疫治疗靶点的范围，将囊括非免疫原性细胞内的肿瘤蛋白，并可以在临床环境中通过靶向更多的HLA异型进行治疗。

据了解，大多数致癌因子都是细胞内蛋白，这限制了利用免疫疗法靶向由单个人类白细胞抗原异型呈现的突变肽（新抗原）。然而，大多数癌症具有较小的突变负荷，不足以产生基于新抗原疗法的反应。神经母细胞瘤是一种儿科癌症，它很少发生突变，而是由表观遗传转录网络失调诱导。

附：英文原文

Title: Targeting of intracellular oncoproteins with peptide-centric CARs

Author: Yarmarkovich, Mark, Marshall, Quinlen F., Warrington, John M., Premaratne, Rasika, Farrel, Alvin, Groff, David, Li, Wei, di Marco, Moreno, Runbeck, Erin, Truong, Hau, Toor, Jugmohit S., Tripathi, Sarvind, Nguyen, Son, Shen, Helena, Noel, Tiffany, Church, Nicole L., Weiner, Amber, Kendsersky, Nathan, Martinez, Dan, Weisberg, Rebecca, Christie, Molly, Eisenlohr, Laurence, Bosse, Kristopher R., Dimitrov, Dimiter S., Stevanovic, Stefan, Sgourakis, Nikolaos G., Kiefel, Ben R., Maris, John M.

Issue&Volume: 2023-11-08

Abstract: The majority of oncogenic drivers are intracellular proteins, constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient for generating responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins essential for tumorigenesis. We focused on targeting the unmutated peptide QYNPIRTTF discovered on HLA-A*24:02, which is derived from the neuroblastoma-dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (PC-CARs) through a counter panning strategy using predicted potentially cross-reactive peptides. We further proposed that PC-CARs can recognize peptides on additional HLA allotypes when presenting a similar overall molecular surface. Informed by our computational modelling results, we show that PHOX2B PC-CARs also recognize QYNPIRTTF presented by HLA-A*23:01, the most common non-A2 allele in people with African ancestry. Finally, we demonstrate potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that PC-CARs have the potential to expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and allow targeting through additional HLA allotypes in a clinical setting. Peptide-centric chimeric antigen receptors (PC-CARs) provide a platform to address the challenges involved in targeting intracellular oncoproteins, and PC-CARs based on the neuroblastoma-dependency gene PHOX2B induce elimination of aggressive tumors.

DOI: 10.1038/s41586-023-06706-0

Source: https://www.nature.com/articles/s41586-023-06706-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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