Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.
Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.
复制标题
DOI：
10.1016/s1470-2045(21)00245-x
复制
发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Lesniak MS
中科院分区：
文献类型：
--
作者：
Fares J;Ahmed AU;Ulasov IV;Sonabend AM;Miska J;Lee-Chang C;Balyasnikova IV;Chandler JP;Portnow J;Tate MC;Kumthekar P;Lukas RV;Grimm SA;Adams AK;Hébert CD;Strong TV;Amidei C;Arrieta VA;Zannikou M;Horbinski C;Zhang H;Burdett KB;Curiel DT;Sachdev S;Aboody KS;Stupp R;Lesniak MS
Malignant glioma is the most common and lethal primary brain tumor, with dismal survival rates and no effective treatment. We examined the safety and therapeutic potential of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma. A first-in-human, open-label, phase 1, dose-escalation clinical trial was conducted to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3+3 design. Patients with newly diagnosed high-grade gliomas (WHO Grade III or IV), confirmed by histological testing, were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received the first dose level starting at 6.25×1010 viral particles (vp) administered via 50 million NSCs, followed by the second patient cohort with the second dose level of 1.25×1011 vp administered via 100 million NSCs, and the third cohort received 1.875×1011 vp administered via 150 million NSCs. No further dose escalation was planned. Within 10–14 days, treatment with temozolomide and radiotherapy was initiated. Assessment was done through medical history, imaging, blood samples, and chemistry values that were collected at screening and follow-up. Tissue analysis for cytokines and immune infiltrates was also performed. Primary endpoints were safety and tolerability. Secondary endpoints included the estimation of survival outcomes in patients, and the evaluation of whether clinical outcomes correlated with the extent of the immune response. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134. Between April 24, 2017 and November 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. The median follow-up was 18 months (IQR 14–22). Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. Treatment was safe as no formal dose-limiting toxicity was reached. One patient developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Post-mortem tissue exploration showed that NSC-CRAd-S-pk7 was effectively cleared from the brain. There were no treatment related deaths. The median progression-free survival and overall survival were 9.05 months (95% CI 8.54, NA) and 18.4 months (95% CI 15.7, NA), respectively. NSC-CRAd-S-pk7 elicited an immune-mediated anti-glioma response and showed promising survival outcomes, especially in patients with MGMT unmethylated tumors. Exploratory immunological results support continued investigation of NSC-CRAd-S-pk7 with multiple injections through an intracranial catheter and/or its combination with anti-PD-1 immunotherapy in a higher phase trial with a larger cohort of patients.
