Translational Brain Tumor Immunotherapy Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts.
Neuro Oncol. 2018 Jan 10;20(1):44-54. doi: 10.1093/neuonc/nox125.
Glioma immunotherapy is an active area of clinical investigation. Glioma-associated immunosuppression remains an obstacle to efficacious immunotherapy, and combination approaches are likely necessary for durable success. OX40 is a member of the tumor necrosis factor receptor superfamily that is upregulated on activated lymphocytes, ligation of which results in enhanced activity and may be active against cancer. We sought to confirm the efficacy of agonist anti-OX40 immunotherapy against glioma and hypothesized that it is complementary with irradiated whole tumor cell vaccination.
GL261 tumor cells were implanted into the right frontal lobes of syngeneic mice, which were then treated with controls, agonist anti-OX40 monoclonal antibody, vaccination with subcutaneous injection of irradiated granulocyte macrophage colony stimulating factor (GM-CSF)-expressing GL261 cells (GVAX), or vaccination + agonist anti-OX40 therapy. Animals were followed for survival. On day 18, splenocytes were harvested for enzyme-linked immunosorbent spot analyses and brains were harvested for immunohistochemistry and flow cytometry analyses of infiltrating lymphocytes.
Combination immunotherapy with GVAX and systemic agonist anti-OX40 monoclonal antibody improved survival by 14 days over controls (median survival 36 vs 22 days, P < 0.00005). Systemically, T helper cell type 1 (Th1) antitumor immunity was enhanced significantly by combination therapy. In the brain, combination immunotherapy increased the percentage of Th1 CD4+ T lymphocytes and reduced the fraction that were Th2. In the brain, vaccination improved the ratio of CD8+ to FoxP3+ T lymphocytes, while combination immunotherapy reversed intracranial T-lymphocyte exhaustion, reducing their coexpression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as well as PD-1 and lymphocyte-activation gene 3 (LAG-3).
Anti-OX40 immunotherapy is active against intracranial glioma and synergizes with GVAX. Vaccination and anti-OX40 immunotherapy are mechanistically complementary, particularly in the glioma microenvironment.
神经胶质瘤免疫疗法是临床研究的一个活跃领域。神经胶质瘤相关的免疫抑制仍然是有效免疫治疗的障碍，因此可能需要联合治疗方法才能取得持久的成功。OX40 是肿瘤坏死因子受体超家族的成员，在活化的淋巴细胞上上调，其配体的结合导致活性增强，并且可能对癌症有效。我们试图证实激动型抗-OX40 免疫疗法对神经胶质瘤的疗效，并假设它与放射性全肿瘤细胞疫苗接种具有互补性。
将 GL261 肿瘤细胞植入同基因小鼠的右侧额叶，然后用对照、激动型抗-OX40 单克隆抗体、皮下注射表达粒细胞巨噬细胞集落刺激因子（GM-CSF）的 GL261 细胞（GVAX）疫苗、或疫苗接种+激动型抗-OX40 治疗进行治疗。对动物进行生存随访。在第 18 天，采集脾细胞进行酶联免疫斑点分析，采集大脑进行浸润淋巴细胞的免疫组化和流式细胞术分析。
GVAX 和全身激动型抗-OX40 单克隆抗体联合免疫治疗使对照组的生存时间延长了 14 天（中位生存时间 36 天 vs 22 天，P < 0.00005）。全身 Th1 抗肿瘤免疫显著增强。在大脑中，联合免疫治疗增加了 Th1 CD4+T 淋巴细胞的比例，减少了 Th2 细胞的比例。疫苗接种改善了 CD8+与 FoxP3+T 淋巴细胞的比例，而联合免疫治疗则逆转了颅内 T 淋巴细胞衰竭，减少了其程序性细胞死亡蛋白 1（PD-1）和 T 细胞免疫球蛋白和粘蛋白结构域 3（TIM-3）以及 PD-1 和淋巴细胞激活基因 3（LAG-3）的共表达。
抗-OX40 免疫疗法对颅内神经胶质瘤有效，并与 GVAX 具有协同作用。疫苗接种和抗-OX40 免疫疗法在机制上是互补的，特别是在神经胶质瘤微环境中。
