Yagiz Kader, Huang Tiffany T, Lopez Espinoza Fernando, Mendoza Daniel, Ibañez Carlos E, Gruber Harry E, Jolly Douglas J, Robbins Joan M
Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.)
Tocagen Inc., San Diego, California (K.Y., T.T.H., F.L.E., D.M., C.E.I., H.E.G., D.J.J., J.M.R.).
Neuro Oncol. 2016 Oct;18(10):1390-401. doi: 10.1093/neuonc/now089. Epub 2016 May 10.
Toca 511, a gamma retroviral replicating vector encoding cytosine deaminase, used in combination with 5-fluorocytosine (5-FC) kills tumor by local production of 5-fluorouracil (5-FU), inducing local and systemic immunotherapeutic response resulting in long-term survival after cessation of 5-FC. Toca 511 and Toca FC (oral extended-release 5-FC) are under investigation in patients with recurrent high-grade glioma. Lomustine is a treatment option for patients with high-grade glioma.
We investigated the effects of lomustine combined with Toca 511 + 5-FC in syngeneic orthotopic glioma models. Safety and survival were evaluated in immune-competent rat F98 and mouse Tu-2449 models comparing Toca 511 + 5-FC to lomustine + 5-FC or the combination of Toca 511 + 5-FC + lomustine. After intracranial implantation of tumor, Toca 511 was delivered transcranially followed by cycles of intraperitoneal 5-FC with or without lomustine at the first or fourth cycle.
Coadministration of 5-FC with lomustine was well tolerated. In F98, combination Toca 511 + 5-FC and lomustine increased median survival, but "cures" were not achieved. In Tu-2449, combination Toca 511 + 5-FC and lomustine increased median survival and resulted in high numbers of cure. Rejection of tumor rechallenge occurred after treatment with Toca 511 + 5-FC or combined with lomustine, but not with lomustine + 5-FC. Mixed lymphocyte-tumor cell reactions using splenocytes from cured animals showed robust killing of target cells in an effector:target ratio-dependent manner with Toca 511 + 5-FC and Toca 511 + 5-FC + lomustine day 10.
The combination of Toca 511 + 5-FC and lomustine shows promising efficacy with no additive toxicity in murine glioma models. Immunotherapeutic responses resulting in long-term survival were preserved despite lomustine-related myelosuppression.
Toca 511是一种编码胞嘧啶脱氨酶的γ逆转录病毒复制载体，与5-氟胞嘧啶（5-FC）联合使用可通过局部产生5-氟尿嘧啶（5-FU）杀死肿瘤，诱导局部和全身免疫治疗反应，从而在停用5-FC后实现长期生存。Toca 511和Toca FC（口服缓释5-FC）正在复发性高级别胶质瘤患者中进行研究。洛莫司汀是高级别胶质瘤患者的一种治疗选择。
我们在同基因原位胶质瘤模型中研究了洛莫司汀联合Toca 511 + 5-FC的效果。在免疫健全的大鼠F98和小鼠Tu-2449模型中评估安全性和生存率，将Toca 511 + 5-FC与洛莫司汀 + 5-FC或Toca 511 + 5-FC + 洛莫司汀的组合进行比较。肿瘤颅内植入后，经颅给予Toca 511，随后在第一个或第四个周期进行腹腔注射5-FC，同时或不同时使用洛莫司汀。
5-FC与洛莫司汀联合给药耐受性良好。在F98模型中，Toca 511 + 5-FC与洛莫司汀联合使用可提高中位生存期，但未实现“治愈”。在Tu-2449模型中，Toca 511 + 5-FC与洛莫司汀联合使用可提高中位生存期并导致大量治愈病例。用Toca 511 + 5-FC或与洛莫司汀联合治疗后出现肿瘤再激发排斥反应，但洛莫司汀 + 5-FC治疗后未出现。使用治愈动物的脾细胞进行的混合淋巴细胞-肿瘤细胞反应显示，在第10天，Toca 511 + 5-FC和Toca 511 + 5-FC + 洛莫司汀以效应细胞：靶细胞比例依赖性方式对靶细胞有强大的杀伤作用。
在小鼠胶质瘤模型中，Toca 511 + 5-FC与洛莫司汀联合使用显示出有前景的疗效且无附加毒性。尽管存在洛莫司汀相关的骨髓抑制，但仍保留了导致长期生存的免疫治疗反应。
