Immunology Research Area, IRCCS Bambino Gesù Children's Hospital, Viale San Paolo 15, 00146, Rome, Italy.
Department of Pediatric Hematology and Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Piazza Sant'Onofrio, 4, 00165, Rome, Italy.
J Hematol Oncol. 2021 Nov 12;14(1):191. doi: 10.1186/s13045-021-01193-0.
The outcome of patients affected by high-risk or metastatic neuroblastoma (NB) remains grim, with ≥ 50% of the children experiencing relapse or progression of the disease despite multimodal, intensive treatment. In order to identify new strategies to improve the overall survival and the quality of life of these children, we recently developed and optimized a third-generation GD2-specific chimeric antigen receptor (CAR) construct, which is currently under evaluation in our Institution in a phase I/II clinical trial (NCT03373097) enrolling patients with relapsed/refractory NB. We observed that our CAR T-cells are able to induce marked tumor reduction and even achieve complete remission with a higher efficiency than that of other CAR T-cells reported in previous studies. However, often responses are not sustained and relapses occur. Here, we demonstrate for the first time a mechanism of resistance to GD2.CAR T-cell treatment, showing how polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) increase in the peripheral blood (PB) of NB patients after GD2.CAR T-cell treatment in case of relapse and loss of response. In vitro, isolated PMN-MDSC demonstrate to inhibit the anti-tumor cytotoxicity of different generations of GD2.CAR T-cells. Gene-expression profiling of GD2.CAR T-cells "conditioned" with PMN-MDSC shows downregulation of genes involved in cell activation, signal transduction, inflammation and cytokine/chemokine secretion. Analysis of NB gene-expression dataset confirms a correlation between expression of these genes and patient outcome. Moreover, in patients treated with GD2.CAR T-cells, the frequency of circulating PMN-MDSC inversely correlates with the levels of GD2.CAR T-cells, resulting more elevated in patients who did not respond or lost response to the treatment. The presence and the frequency of PMN-MDSC in PB of high-risk and metastatic NB represents a useful prognostic marker to predict the response to GD2.CAR T-cells and other adoptive immunotherapy. This study underlines the importance of further optimization of both CAR T-cells and clinical trial in order to target elements of the tumor microenvironment.
患有高危或转移性神经母细胞瘤 (NB) 的患者的预后仍然不容乐观，尽管采用了多模式、强化治疗，仍有≥50%的儿童出现疾病复发或进展。为了寻找新的策略来提高这些儿童的总生存率和生活质量，我们最近开发并优化了第三代 GD2 特异性嵌合抗原受体 (CAR) 构建体，目前正在我们机构的一项 I/II 期临床试验（NCT03373097）中进行评估，该试验招募了复发/难治性 NB 患者。我们观察到，与之前研究中报道的其他 CAR T 细胞相比，我们的 CAR T 细胞能够更有效地诱导明显的肿瘤缩小，甚至实现完全缓解。然而，反应往往不能持续，疾病会复发。在这里，我们首次证明了 GD2.CAR T 细胞治疗的耐药机制，表明在复发和反应丧失时，GD2.CAR T 细胞治疗后 NB 患者外周血（PB）中的多形核髓系来源的抑制细胞（PMN-MDSC）如何增加。体外实验表明，分离的 PMN-MDSC 抑制不同代 GD2.CAR T 细胞的抗肿瘤细胞毒性。用 PMN-MDSC“调节”的 GD2.CAR T 细胞的基因表达谱显示，参与细胞激活、信号转导、炎症和细胞因子/趋化因子分泌的基因下调。对 GD2.CAR T 细胞“调节”的 NB 基因表达数据集的分析证实了这些基因的表达与患者结局之间存在相关性。此外，在接受 GD2.CAR T 细胞治疗的患者中，循环 PMN-MDSC 的频率与 GD2.CAR T 细胞的水平呈反比，在对治疗无反应或反应丧失的患者中更为升高。高危和转移性 NB 患者 PB 中 PMN-MDSC 的存在和频率是预测对 GD2.CAR T 细胞和其他过继免疫治疗反应的有用预后标志物。这项研究强调了进一步优化 CAR T 细胞和临床试验以靶向肿瘤微环境的重要性。
