IGV-001 是一种定制的自体癌细胞免疫疗法，旨在向脑胶质母细胞瘤（GBM）患者输送肿瘤源性抗原负载和免疫刺激信号。IGV-001 由经胰岛素样生长因子1受体（IGF1R）反义寡聚脱氧核苷酸处理的患者来源的 GBM 细胞构成，并置于专有的生物扩散室（BDC）中。然后，将 BDC 暴露于5-6 Gy 放射线，并在腹部位置植入约48小时。IGV-001 在早期诊断的 GBM 患者中以前已被证明在临床上具有很好的安全性和良好的治疗效果。 使用 GL261 小鼠 GBM 细胞或人类 GBM 细胞制备了 IGV-001 的小鼠（m）和人类（h）变体。在预防性和治疗性实验中，将含有载体或 mIGV-001 的 BDC 植入 C57BL/6 白化雌性小鼠的侧腹，并可选择与编程细胞死亡1（PD-1）阻断剂组合使用。还对肝细胞癌 Hepa 1-6 细胞进行了普遍方法的生物活性测量。跟踪小鼠接受 mIGV-001 后随后植入或已有肿瘤的生长情况和生存状况。对接受 mIGV-001 的小鼠进行了免疫表型分析。对 mIGV-001 和 hIGV-001 进行了细胞外 ATP 和高迁移率族群盒1（HMGB1）的分析，作为免疫原性细胞死亡（ICD）指标，同时还进行了细胞活力、表面类钙蛋白和活性氧化物的流式细胞术分析。通过免疫印迹分析压力和细胞死亡相关途径。 IGV-001 在 GL261 细胞中引起氧化应激和内质网应激，导致细胞毒性反应，使抗原性材料和免疫刺激、与 ICD 相关分子（包括 ATP 和 HMGB1）从 BDC 中释放出来。免疫表型分析证实，IGV-001 增加了 BDC 引流淋巴结中树突状细胞的百分比，以及效应细胞和效应记忆 T 细胞的百分比。与这些观察结果一致，预防性 IGV-001 在小鼠颅内注射 GL261 细胞的挑战下限制了肿瘤的进展，并延长了总生存期，这一益处与具有效应特征的肿瘤特异性 T 细胞的增加有关。在 Hepa 1-6 模型中也得到了类似的发现。此外，治疗性地给予 IGV-001，并与 PD-1 组合使用，可以延缓 GBM 携带小鼠的疾病进展。 这些结果支持使用 IGV-001 诱导临床相关的 ICD 驱动的GBM患者体内抗癌免疫反应。© 作者(或其雇主) 2023。CC BY-NC 许可再使用。不得用于商业用途。请参阅权利和权限。由 BMJ 出版。

IGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived GBM cells treated with an antisense oligodeoxynucleotide against insulin-like growth factor 1 receptor (IGF1R) and placed in proprietary biodiffusion chambers (BDCs). The BDCs are then exposed to 5-6 Gy radiation and implanted at abdominal sites for ~48 hours. IGV-001 has previously been shown to be generally safe with promising clinical activity in newly diagnosed GBM patients.Mouse (m) or human (h) variants of IGV-001 were prepared using GL261 mouse GBM cells or human GBM cells, respectively. BDCs containing vehicle or mIGV-001 were implanted in the flanks of C57BL/6 albino female mice in preventative and therapeutic experiments, optionally in combination with a programmed cell death 1 (PD-1) blocker. Bioactivity of the general approach was also measured against hepatocellular carcinoma Hepa 1-6 cells. Mice were followed for the growth of subsequently implanted or pre-existing tumors and survival. Draining lymph nodes from mice receiving mIGV-001 were immunophenotyped. mIGV-001 and hIGV-001 were analyzed for extracellular ATP and high mobility group box 1 (HMGB1) as indicators of immunogenic cell death (ICD), along with flow cytometric analysis of viability, surface calreticulin, and reactive oxygen species. Stress and cell death-related pathways were analyzed by immunoblotting.IGV-001 causes oxidative and endoplasmic reticulum stress in GL261 cells, resulting in a cytotoxic response that enables the release of antigenic material and immunostimulatory, ICD-associated molecules including ATP and HMGB1 from BDCs. Immunophenotyping confirmed that IGV-001 increases the percentage of dendritic cells, as well as effector, and effector memory T cells in BDC-draining lymph nodes. Consistent with these observations, preventative IGV-001 limited tumor progression and extended overall survival in mice intracranially challenged with GL261 cells, a benefit that was associated with an increase in tumor-specific T cells with effector features. Similar findings were obtained in the Hepa 1-6 model. Moreover, therapeutically administered IGV-001 combined with PD-1 delayed progression in GBM-bearing mice.These results support treatment with IGV-001 to induce clinically relevant ICD-driven anticancer immune responses in patients with GBM.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.