Department of Anesthesiology, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02144.
Department of Microbiology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2022 Jun 14;119(24):e2202719119. doi: 10.1073/pnas.2202719119. Epub 2022 Jun 8.
Schwannomas are slow-growing benign neoplasms that develop throughout the body causing pain, sensory/motor dysfunction, and death. Because bacterial immunotherapy has been used in the treatment of some malignant neoplasms, we evaluated attenuated strains as immunotherapies for benign murine schwannomas. Several bacterial strains were tested, including VNP20009, a highly attenuated strain that was previously shown to be safe in human subjects with advanced malignant neoplasms, and a VNP20009 mutant that was altered in motility and other properties that included adherence and invasion of cultured mammalian cells. VNP20009 controlled tumor growth in two murine schwannoma models and induced changes in cytokine and immune effector cell profiles that were consistent with induction of enhanced innate and adaptive host immune responses compared with controls. Intratumoral (i.t.) injection of led to tumor cell apoptosis, decreased tumor angiogenesis, and lower growth of the injected schwannoma tumors. Invasive VNP20009 was significantly more efficacious than was a noninvasive derivative in controlling the growth of injected tumors. Bacterial treatment apparently induced systemic antitumor immunity in that the growth of rechallenge schwannomas implanted following primary bacterial treatment was also reduced. Checkpoint programmed death-1 (PD-1) blockade induced by systemic administration of anti-PD-1 antibodies controlled tumor growth to the same degree as i.t. injection of , and together, these two therapies had an additive effect on suppressing schwannoma growth. These experiments represent validation of a bacterial therapy for a benign neoplasm and support development of VNP20009, potentially in combination with PD-1 inhibition, as a schwannoma immunotherapy.
雪旺细胞瘤是一种生长缓慢的良性肿瘤，可在全身各处生长，导致疼痛、感觉/运动功能障碍和死亡。由于细菌免疫疗法已被用于治疗某些恶性肿瘤，我们评估了减毒菌株作为治疗良性小鼠雪旺细胞瘤的免疫疗法。测试了几种细菌菌株，包括 VNP20009，这是一种高度减毒的菌株，以前在晚期恶性肿瘤的人类受试者中被证明是安全的，以及一种在运动性和其他特性（包括对培养的哺乳动物细胞的粘附和入侵）上发生改变的 VNP20009 突变体。VNP20009 控制了两种小鼠雪旺细胞瘤模型中的肿瘤生长，并诱导了细胞因子和免疫效应细胞谱的变化，与对照相比，这些变化与增强先天和适应性宿主免疫反应的诱导一致。肿瘤内（i.t.）注射 导致肿瘤细胞凋亡、肿瘤血管生成减少和注射的雪旺细胞瘤生长降低。侵袭性 VNP20009 比非侵袭性衍生物更有效地控制注射肿瘤的生长。细菌治疗显然诱导了全身抗肿瘤免疫，因为在初次细菌治疗后植入的复发性雪旺细胞瘤的生长也减少了。系统给予抗 PD-1 抗体诱导的检查点程序性死亡-1（PD-1）阻断将肿瘤生长控制到与 i.t.注射 相同的程度，并且这两种疗法对抑制雪旺细胞瘤生长具有相加作用。这些实验验证了细菌疗法治疗良性肿瘤的有效性，并支持开发 VNP20009，可能与 PD-1 抑制联合使用，作为雪旺细胞瘤的免疫疗法。
