Safety and efficacy of dendritic cell-based immunotherapy DCVAC/OvCa added to first-line chemotherapy (carboplatin plus paclitaxel) for epithelial ovarian cancer: a phase 2, open-label, multicenter, randomized trial

Abstract

BackgroundMost patients with epithelial ovarian cancer (EOC) relapse despite primary debulking surgery and chemotherapy (CT). Autologous dendritic cell immunotherapy (DCVAC) can present tumor antigens to elicit a durable immune response. We hypothesized that adding parallel or sequential DCVAC to CT stimulates antitumor immunity and improves clinical outcomes in patients with EOC. Based on the interim results of sequential DCVAC/OvCa administration and to accommodate the increased interest in maintenance treatment in EOC, the trial was amended by adding Part 2.MethodsPatients with International Federation of Gynecology and Obstetrics stage III EOC (serous, endometrioid, or mucinous), who underwent cytoreductive surgery up to 3 weeks prior to randomization and were scheduled for first-line platinum-based CT were eligible. Patients, stratified by tumor residuum (0 or <1 cm), were randomized (1:1:1) to DCVAC/OvCa parallel to CT (Group A), DCVAC/OvCa sequential to CT (Group B), or CT alone (Group C) in Part 1, and to Groups B and C in Part 2. Autologous dendritic cells for DCVAC were differentiated from patients’ CD14+ monocytes, pulsed with two allogenic OvCa cell lines (SK-OV-3, OV-90), and matured in the presence of polyinosinic:polycytidylic acid. We report the safety outcomes (safety analysis set, Parts 1 and 2 combined) along with the primary (progression-free survival (PFS)) and secondary (overall survival (OS)) efficacy endpoints. Efficacy endpoints were assessed in the modified intention-to-treat (mITT) analysis set in Part 1.ResultsBetween November 2013 and March 2016, 99 patients were randomized. The mITT (Part 1) comprised 31, 29, and 30 patients in Groups A, B, and C, respectively. Baseline characteristics and DCVAC/OvCa exposure were comparable across the treatment arms. DCVAC/OvCa showed a good safety profile with treatment-emergent adverse events related to DCVAC/OvCa in 2 of 34 patients (5.9%) in Group A and 2 of 53 patients (3.8%) in Group B. Median PFS was 20.3, not reached, and 21.4 months in Groups A, B, and C, respectively. The HR (95% CI) for Group A versus Group C was 0.98 (0.48 to 2.00; p=0.9483) and the HR for Group B versus Group C was 0.39 (0.16 to 0.96; p=0.0336). This was accompanied by a non-significant trend of improved OS in Groups A and B. Median OS was not reached in any group after a median follow-up of 66 months (34% of events).ConclusionsDCVAC/OvCa and leukapheresis was not associated with significant safety concerns in this trial. DCVAC/OvCa sequential to CT was associated with a statistically significant improvement in PFS in patients undergoing first-line treatment of EOC.Trial registration numberNCT02107937, EudraCT2010-021462-30.

Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines

“…We recently published the results of three independent open-label, randomized Phase I/II, II and III clinical studies that compared the efficacy of an autologous DC-based vaccine (DCVAC) delivered in the context of standard of care chemotherapy (SOC) versus SOC alone in patients with advanced non-small cell lung carcinoma (NSCLC; SLU01, NCT02470468), 21 epithelial ovarian cancer (EOC; SOV01, NCT02107937), 22 , 23 or metastatic castration-resistant prostate cancer (mCRPC; SP005, NCT02111577). 24 In these settings, DCVAC was well tolerated and significantly extended the progression-free survival (PFS) and overall survival (OS) of EOC or NSCLC patients.…”

“… 24 In these settings, DCVAC was well tolerated and significantly extended the progression-free survival (PFS) and overall survival (OS) of EOC or NSCLC patients. 21 , 22 In mCRPC patients, DCVAC combined with SOC and continued as maintenance treatment showed a favorable safety profile but did not extend OS. 24 …”

“…Patients in arm C (n = 31) received SOC alone. 22 The designs of these studies are briefly described in the Supplemental Materials and Methods. In SP005 and SLU01, the primary endpoint was overall survival (OS) defined as the time from randomization until death due to any cause.…”

“…The results of all three clinical trials have been reported. 21 , 22 , 24 The baseline characteristics for patients included in this study were similar across the relevant treatment groups (Supplemental Table 1).…”

Identification of an Immune Gene-Based Cisplatin Response Model and CD27 as a Therapeutic Target against Cisplatin Resistance for Ovarian Cancer

“…Increasing evidence demonstrates that both the type and extent of immune infiltration correlate with OV patients' outcome [ 23 ]. In a recent clinical trial, the addition of dendritic cell-based immunotherapy to the first-line chemotherapy (carboplatin plus paclitaxel) significantly improved progression-free survival of epithelial OV patients [ 24 ]. Resolution of immune cells in the exudate of OV patients revealed that higher proportions of B cells and NK cells corresponded to worse patient survival, with the coincidence of higher B cells in FIGO stage IV patients than in stage III [ 25 ].…”