Ribeiro Ana R, Britton-Rivet Camille, Collins Laura, Carreira Ricardo J, Moureau Sylvie, Benlahrech Adel, Stanhope Sarah, Harper Stephen, Liddy Nathaniel, Mahon Tara M, Petrovic Kristina, Fife Mark, Depoil David, Addis Philip, Bedke Nicole, Bouard Lucie, O'Dwyer Ronan, Gascoyne Duncan, Ranade Koustubh
Immunocore Limited, Abingdon, Oxfordshire, United Kingdom.
Immunother Adv. 2024 Nov 2;4(1):ltae008. doi: 10.1093/immadv/ltae008. eCollection 2024.
PRAME (eferentially expressed ntigen in lanoma) is a cancer-testis antigen expressed in several tumor indications, representing an attractive anticancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME tumors could be a novel immunotherapeutic option. We confirm that PRAME protein is expressed in cutaneous melanoma, including rare subtypes with limited treatment options, as well as primary and metastatic lung, breast, endometrial, and ovarian tumors. Furthermore, PRAME is expressed homogeneously across tumors with distinct oncogenic mutations, mutation burden, PD-L1 expression, immune infiltration, and features of immune checkpoint resistance. Immunopeptidomic analysis of primary tumors detected HLA class I-restricted PRAME peptides.
A TCR recognizing PRAME peptide SLLQHLIGL was engineered to high affinity and fused to a CD3 engaging domain to create a TCRxCD3 bispecific molecule (mmune-obilizing onoclonal TCR gainst ancer, ImmTAC®) with the ability to redirect polyclonal T cells to efficiently kill PRAME cells.
The degree of T cell activation was positively correlated with peptide-HLA abundance, with as few as 10 epitopes per cell sufficient for target cell killing. Impaired ImmTAC®-redirected cytotoxicity of exhausted T cells was rescued using an anti-PD-1 antibody, supporting the use of a combination strategy to treat tumors with active PDL1-PD1 axes.
Our data demonstrate selective and efficient T cell activation and killing by a PRAME-directed TCRxCD3 bispecific, supporting further investigation in multiple cancer indications.
PRAME（黑色素瘤优先表达抗原）是一种在多种肿瘤指征中表达的癌胚抗原，是一个有吸引力的抗癌靶点。然而，其细胞内定位限制了传统方法的靶向作用。PRAME肽通过人类白细胞抗原（HLA）分子呈递在肿瘤细胞表面，这表明基于T细胞受体（TCR）的策略，即将T细胞重定向以杀伤PRAME肿瘤，可能是一种新型免疫治疗选择。我们证实PRAME蛋白在皮肤黑色素瘤中表达，包括治疗选择有限的罕见亚型，以及原发性和转移性肺、乳腺、子宫内膜和卵巢肿瘤。此外，PRAME在具有不同致癌突变、突变负荷、PD-L1表达、免疫浸润和免疫检查点抵抗特征的肿瘤中均呈均匀表达。对原发性肿瘤的免疫肽组学分析检测到了HLA I类限制性PRAME肽。
设计一种识别PRAME肽SLLQHLIGL的TCR，使其具有高亲和力，并与一个CD3结合结构域融合，以创建一个TCRxCD3双特异性分子（免疫动员单克隆TCR抗癌，ImmTAC®），该分子能够重定向多克隆T细胞以有效杀伤PRAME细胞。
T细胞活化程度与肽-HLA丰度呈正相关，每个细胞低至10个表位就足以杀伤靶细胞。使用抗PD-1抗体挽救了耗竭T细胞的ImmTAC®重定向细胞毒性受损，支持使用联合策略治疗具有活跃PDL1-PD1轴的肿瘤。
我们的数据表明，PRAME导向的TCRxCD3双特异性分子可实现选择性和高效的T细胞活化及杀伤，支持在多种癌症指征中进行进一步研究。
