CELL INTELLIGENCE · 肿瘤细胞治疗研究

This study investigated immune and gene expression modulation of tumor microenvironment (TME) by oncolytic vaccinia virus Olvi-Vec as an immunotherapy and subsequent clinical impact on platinum sensitivity in ovarian cancer (OC). Methods. We studied synergy between platinum and Olvi-Vec in mouse model of platinum-resistant OC (PROC). Subsequently, phase 1b/2 VIRO-15 study was completed in heavily pretreated patients with platinum-resistant/refractory OC (PRROC). To assess Olvi-Vec infection of tumor cells, VIRO-15 patients' ascitic fluid was analyzed by cytology. To evaluate changes in gene expression patterns, paired tumor biopsies obtained before and after Olvi-Vec treatment were analyzed by multiplex immunohistochemistry (IHC) and RNA profiling. Progression-free survival (PFS) from phase-2 patients were compared to their last line of platinum therapy.

In the preclinical study, durable antitumor effect was achieved through combination treatment with Olvi-Vec and cisplatin in mouse model of PROC. Cytologic analysis in VIRO-15 showed viral infection and eradication of tumor cells in patients' ascitic fluid. Multiplex IHC analysis demonstrated large influx of CD8+ tumor-infiltrating lymphocytes activated by Olvi-Vec. RNA profiling analysis identified expression of genes in tumors that were down-regulated or up-regulated after Olvi-Vec treatment. These transcriptional changes suggest four biologically relevant expression patterns associated with immune activation, viral infection, sensitization to chemotherapy, anticancer activity and survival. Combination therapy of Olvi-Vec and platinum-doublet chemotherapy resulted in a clinically meaningful benefit in the VIRO-15 study, reversing the typical trend of deteriorating PFS, and with clinical reversal of platinum resistance.

Olvi-Vec treatment can favorably modify the TME in OC and may explain the apparent reversal of platinum resistance following platinum rechallenge. Trial Registration: ClinicalTrials.gov Identifier: NCT02759588.