NT-18PHASE I CLINICAL TRIAL OF ONCOLYTIC VIRUS DELTA-24-RGD (DNX-2401) WITH BIOLOGICAL ENDPOINTS: IMPLICATIONS FOR VIRO-IMMUNOTHERAPY

摘要

Delta-24-RGD is a novel replication-competent, tumor-selective, oncolytic adenovirus with enhanced infectivity. Based on promising preclinical studies, we undertook a first-in-human Phase I clinical trial with biological endpoints in order to assess the capacity of Delta-24-RGD to replicate in human gliomas, and to determine safety and initial efficacy. Patients with recurrent high-grade gliomas were enrolled in one of two arms. Group A (clinical assessment group) received a single intratumoral injection of Delta-24-RGD into biopsy-proven recurrent glioma. Group B (biological endpoint group) received an initial intratumoral injection through an implanted catheter followed 14 days later by en bloc tumor/catheter resection (to obtain post-treatment specimens) and subsequent injection of Delta-24-RGD into the post-resection cavity. Dose was escalated in 8 cohorts (1x10⁷-3x10¹⁰vp). Histological analysis of post-treatment en bloc surgical specimens proved for the first time that Delta-24-RGD is capable of infecting, replicating in, and killing/lysing glioma tumor cells (Group B; N = 12). Delta-24-RGD resulted in no toxicity and the MTD was 3 × 10¹⁰vp (Group A; N = 25). Outcome analyses show an overall median survival of 11 months. Remarkably, complete responses were seen in 3 patients (12%) all of whom are still alive with no evidence of disease 3.2, 2 and 1.75 years after treatment. Serial MRIs revealed increased enhancement before tumor regression, consistent with inflammatory-mediated responses. Histological analysis of resected tumor from a symptomatic patient in Arm A during the period of increased MRI-enhancement identified macrophages and CD8 T-cells with only rare tumor cells. Compared with all other patients, the 3-responders had 10-fold to 1000-fold increases in Interleukin-12p70 (which induces Th1-responses and cell-mediated immunity). In conclusion, Delta-24-RGD is a new oncolytic virus with a favorable toxicity-profile that is capable of cycles of infection-replication-lysis in human glioma cells, and that can produce durable complete-responses in subsets of patients. Viral-induced anti-tumor-immunity likely plays a role in the anti-glioma effect.