Vaccination Targeting Native Receptors to Enhance the Function and Proliferation of Chimeric Antigen Receptor (CAR)-Modified T Cells.
Vaccination Targeting Native Receptors to Enhance the Function and Proliferation of Chimeric Antigen Receptor (CAR)-Modified T Cells.
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DOI：
10.1158/1078-0432.ccr-16-2138
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发表时间：
2017-07-15
期刊：
影响因子：
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通讯作者：
Rooney CM
中科院分区：
文献类型：
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作者：
Tanaka M;Tashiro H;Omer B;Lapteva N;Ando J;Ngo M;Mehta B;Dotti G;Kinchington PR;Leen AM;Rossig C;Rooney CM
实体瘤用于抑制肿瘤特异性免疫反应的多种机制是过继转移肿瘤特异性 T 细胞成功的主要障碍。由于病毒诱导有效的先天性和适应性免疫反应，我们假设，如果用肿瘤特异性嵌合抗原受体（CAR）修饰病毒特异性T细胞（VST），则可以利用病毒的免疫原性来治疗实体瘤。我们使用表达 GD2 的 CAR 的 VZV 特异性 T 细胞 (VZVST) 测试了这一假设，GD2 是一种在神经母细胞瘤和某些其他肿瘤上表达的二唾液酸神经节苷脂，因为减毒活 VZV 疫苗可用于体内刺激。我们通过使用跨越所选 VZV 抗原的重叠肽库进行刺激，从健康供体和癌症患者中生成了符合 GMP 要求的 GD2.CAR 修饰的 VZVST，然后测试了它们识别和杀死表达 GD2 和 VZV 抗原的靶细胞的能力。我们对 VZV 抗原的选择通过以下观察得到验证：在接种 VZV 疫苗后，对这些抗原具有特异性的 T 细胞在体内扩增。 VZVST 响应 VZV 抗原分泌细胞因子，杀死 VZV 感染的靶细胞并限制感染性病毒在自体成纤维细胞中的传播。然而，虽然 GD2.CAR 修饰的 VZVST 在第一次遇到时杀死了神经母细胞瘤细胞系，但它们未能在随后的共培养中控制肿瘤细胞。尽管存在这种 CAR 特异性功能障碍，CAR-VZVST 通过其 TCR 和 GD2 保留了对 VZV 抗原的功能特异性。通过 TCR 刺激或暴露于树突状细胞上清液，CAR 功能部分得到恢复。通过 TCR 进行疫苗接种可能提供一种重新激活因肿瘤微环境而功能失调的 CAR-T 细胞的方法。 （NCT01953900）。
The multiple mechanisms used by solid tumors to suppress tumor-specific immune responses are a major barrier to the success of adoptively-transferred tumor-specific T-cells. Since viruses induce potent innate and adaptive immune responses, we hypothesized that the immunogenicity of viruses could be harnessed for the treatment of solid tumors if virus-specific T-cells (VSTs) were modified with tumor-specific chimeric antigen receptors (CARs). We tested this hypothesis using VZV-specific T-cells (VZVSTs) expressing a CAR for GD2, a disialoganglioside expressed on neuroblastoma and certain other tumors, since the live-attenuated VZV vaccine could be used for in vivo stimulation. We generated GMP-compliant, GD2.CAR-modified VZVSTs from healthy donors and cancer patients by stimulation with overlapping peptide libraries spanning selected VZV antigens, then tested their ability to recognize and kill GD2- and VZV antigen-expressing target cells. Our choice of VZV antigens was validated by the observation that T-cells specific for these antigens expanded in vivo after VZV vaccination. VZVSTs secreted cytokines in response to VZV antigens, killed VZV infected target cells and limited infectious virus spread in autologous fibroblasts. However, while GD2.CAR-modified VZVSTs killed neuroblastoma cell lines on their first encounter, they failed to control tumor cells in subsequent cocultures. Despite this CAR-specific dysfunction, CAR-VZVSTs retained functional specificity for VZV antigens via their TCRs and GD2.CAR function was partially rescued by stimulation through the TCR or exposure to dendritic cell supernatants. Vaccination via the TCR may provide a means to reactivate CAR-T-cells rendered dysfunctional by the tumor microenvironment. (NCT01953900).