小柯机器人

美国费城儿童医院John M. Maris团队通过以肽为中心的CAR实现细胞内肿瘤蛋白的交叉HLA靶向。相关论文于2021年11月3日在线发表在《自然》杂志上。

研究人员发现，神经母细胞瘤免疫肽组富含来自肿瘤发生所必需的蛋白肽，并重点针对人类白细胞抗原（HLA）-A*24:02上发现的未突变的肽QYNPIRTTF，该肽来自神经母细胞瘤依赖基因和核心转录调节因子PHOX2B。为了靶向QYNPIRTTF，研究人员利用预测的潜在交叉反应肽的counter-panning策略，开发了以肽为中心的嵌合抗原受体（CAR）。研究人员进一步假设，以肽为中心的CAR在以类似的方式呈现时可以识别其他HLA异型的肽。在计算模型的启发下，结果表明PHOX2B肽中心的CAR也能识别HLA-A*23:01和高度分化的HLA-B*14:02呈现的QYNPIRTTF。

最后，研究人员证明了在体外对表达这些HLA的神经母细胞的强效和特异性杀伤，以及在小鼠体内肿瘤的完全消退。这些数据表明，以肽为中心的CAR有可能极大地扩展免疫治疗靶点库，包括非免疫性的细胞内肿瘤蛋白，并通过打破传统的HLA限制，扩大受益于这种治疗的患者群体。

据介绍，大多数致癌因子是细胞内蛋白，因此限制了它们的免疫治疗目标是由个别HLA异型呈现的变异肽（新抗原）。然而，大多数癌症都有适度的突变负担，不足以使用基于新抗原的疗法产生反应。神经母细胞瘤是一种儿科癌症，其突变很少，而是由表观遗传失调的转录网络驱动。

附：英文原文

Title: Cross-HLA 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: 2021-11-03

Abstract: The majority of oncogenic drivers are intracellular proteins, thus 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 to generate 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 that are essential for tumourigenesis and focus 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 (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.

DOI: 10.1038/s41586-021-04061-6

Source: https://www.nature.com/articles/s41586-021-04061-6

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/
投稿链接：http://www.nature.com/authors/submit_manuscript.html