The efficacy and safety of the combination of axitinib and pembrolizumab-activated autologous DC-CIK cell immunotherapy for patients with advanced renal cell carcinoma: a phase 2 study

Abstract

Objectives: Although axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab-activated autologous dendritic cells-co-cultured cytokine-induced killer cells in patients with advanced RCC.

Methods: All adult patients, including treatment-naive or pretreated with VEGF-targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab-activated dendritic cells-co-cultured cytokine-induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter.

Results: The 43 patients (22 untreated and 21 previously treated) showed a median progression-free survival (mPFS) of 14.7 months (95% CI, 11.16-18.30). mPFS in treatment-naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log-rank P-value = 0.07). Overall response rates were 25.6% (95% CI, 13.5-41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar-plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long-term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8⁺TIM3⁺ T cells and lower serum-level immunostimulatory cytokine profile.

Conclusions: The combination therapy was active and well tolerated for treatment of advanced RCC, either as first- or second-line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers.

Keywords: advanced renal cell carcinoma; axitinib; dendritic cells and cytokine‐induced killer cells immunotherapy; pembrolizumab.

Figure 1

Clinical trial diagram and protocol. (a) Flow diagram illustrating the enrolment and assignment protocols and the analyses performed in the patients in this trial. (b) Overview of the treatment protocol. DC‐CIK, dendritic cells–co‐cultured with cytokine‐induced killer cells; VEGF, vascular endothelial growth factor; W, week.

Figure 2

Clinical outcomes in 43 patients who were treated with axitinib plus pembrolizumab‐activated DC‐CIK cells. (a) Kaplan–Meier survival curve of progression‐free survival (PFS) in (left) overall study population, (middle) treatment‐naive population and (right) targeted agents‐pretreated population. (b) Waterfall plot of the best response in all eligible patients. Twenty‐seven patients (62.8%) had measurable tumor reduction.

Figure 3

Peripheral blood lymphocyte immunophenotype assessment via flow cytometry. (a) Peripheral blood lymphocyte immunophenotype before treatment and after 2 and 4 cycles of pembrolizumab‐activated DC‐CIK cell infusion combination with axitinib treatment (n = 28). (b, c) Peripheral blood lymphocyte immunophenotype after 2 (b) and 4 (c) cycles of pembrolizumab‐activated DC‐CIK cell infusion combination with axitinib treatment in patients with long‐term (n = 18) and minimal (n = 10) survival benefits. DC‐CIK, dendritic cells–co‐cultured with cytokine‐induced killer cells. ns, not significant. *P < 0.05. **P < 0.01. ***P < 0.001. Data are representative of three independent experiments.

Figure 4

Serum cytokine profiles analysis. Serum levels of various cytokines were determined using antibody microarrays, and the fold‐change of each cytokine after pembrolizumab‐activated DC‐CIK cell infusion combination with axitinib treatment versus before treatment was calculated. (a) Heatmap showed differential cytokines of after versus before treatment at the timepoints after 2 and 4 cycles of combination treatment according to the median fold‐change (n = 11). (b) GO analysis for the significant terms enriched by the differential cytokines of before versus after 2 cycles' versus 4 cycles' combination treatment (n = 11). (c) Heatmap showed differential cytokines in the patients with long‐term survival benefit (n = 8) versus minimal survival benefit (n = 3) at timepoints before and after 2 and 4 cycles of combination treatment according to the median fold‐change. (d, e) GO analysis for the significantly top terms enriched by differentially expressed serum cytokines in long‐term survival benefit patients (n = 8) in comparison with minimal survival benefit patients (n = 3) at timepoints of after 2 (d) and 4 (e) cycles of combination treatment. FC, fold‐change. Data are representative of three independent experiments.