DataSheet_1_PD1 Expression in EGFRvIII-Directed CAR T Cell Infusion Product for Glioblastoma Is Associated with Clinical Response.pdf

The epidermal growth factor receptor variant III (EGFRvIII) has been investigated as a therapeutic target for chimeric antigen receptor (CAR) T cell therapy in glioblastoma. Earlier research demonstrated that phenotypic and genotypic characteristics in T cells and CAR T product predicted therapeutic success in hematologic malignancies, to date no determinants for clinical response in solid tumors have been identified. We analyzed apheresis and infusion products from the first-in-human trial of EGFRvIII-directed CAR T for recurrent glioblastoma (NCT02209376) by flow cytometry. Clinical response was quantified via engraftment in peripheral circulation and progression-free survival (PFS), as determined by the time from CAR T infusion to first radiographic evidence of progression. The CD4+CAR T cell population in patient infusion products demonstrated PD1 expression which positively correlated with AUC engraftment and PFS. On immune checkpoint inhibitor analysis, CTLA-4, TIM3, and LAG3 did not exhibit significant associations with engraftment or PFS. The frequencies of PD1+GZMB+ and PD1+HLA-DR+ CAR T cells in the CD4+ infusion products were directly proportional to AUC and PFS. No significant associations were observed within the apheresis products. In summary, PD1 in CAR T infusion products predicted peripheral engraftment and PFS in recurrent glioblastoma.

表皮生长因子受体变异体III（EGFRvIII，epidermal growth factor receptor variant III）已被作为胶质母细胞瘤嵌合抗原受体T细胞疗法（chimeric antigen receptor T cell therapy，CAR）的治疗靶点开展研究。既往研究证实，T细胞与CAR-T产品的表型及基因型特征可预测血液系统恶性肿瘤的治疗效果，但截至目前，尚未有实体瘤临床应答的相关决定因素被探明。我们采用流式细胞术，针对复发性胶质母细胞瘤的首项EGFRvIII靶向CAR-T临床试验（NCT02209376）中的白细胞单采产物与输注产物展开了分析。临床应答通过外周血定植水平与无进展生存期（PFS，progression-free survival）进行量化，其中无进展生存期定义为从CAR-T细胞输注至首次影像学检测到肿瘤进展的时间间隔。患者输注产物中的CD4+CAR-T细胞群表达程序性死亡受体1（PD1，programmed cell death protein 1），其表达水平与定植曲线下面积（AUC，area under the curve）及无进展生存期呈正相关。免疫检查点分子分析显示，细胞毒性T淋巴细胞相关蛋白4（CTLA-4，cytotoxic T-lymphocyte-associated protein 4）、T细胞免疫球蛋白粘蛋白分子3（TIM3，T-cell immunoglobulin and mucin-domain containing-3）及淋巴细胞活化基因3（LAG3，lymphocyte-activation gene 3）的表达与定植水平或无进展生存期均无显著关联。CD4+输注产物中PD1+GZMB+与PD1+HLA-DR+ CAR-T细胞的频率与定植曲线下面积及无进展生存期呈正相关，而白细胞单采产物中未观察到显著关联。综上，CAR-T输注产物中的程序性死亡受体1表达可预测复发性胶质母细胞瘤患者的外周血定植水平与无进展生存期。