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 cytokineinduced 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 treatmentnaive 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.

Antibody‐dependent cell‐mediated cytotoxicity using T cells with NK‐like phenotype in combination with avelumab, an anti‐PD‐L1 antibody

“…Overall, mAb-targeted T-NK cells produced a significant improvement in cytotoxicity that was consistent with the levels of PD-L1 expression on target cells compared to the isotype control. PD-1 is as an inhibitory regulator of T-NK cells and is known to be upregulated on T-NK cells of cancer patients [31,32]. In this regard, blocking of the PD-1/PD-L1 axis improved the intrinsic cytotoxic activity of T-NK cells against PD-L1+ tumour cells, indicating another mode of avelumab action on lymphocytes.…”

“…PD‐1 is as an inhibitory regulator of T‐NK cells and is known to be upregulated on T‐NK cells of cancer patients [31, 32]. In this regard, blocking of the PD‐1/PD‐L1 axis improved the intrinsic cytotoxic activity of T‐NK cells against PD‐L1+ tumour cells, indicating another mode of avelumab action on lymphocytes.…”

XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial

“…In addition, our previous studies have shown that PD1-T cells were active in several kinds of solid tumor, including CRC. 18 , 19 After blocking the PD1/PD-L1 signal pathway with a low dose of pembrolizumab, the cytotoxicity of DC‐CIK cells was enhanced. 18 , 29 …”

“…To overcome the immune barrier of the tumor microenvironment, we developed a novel PD‐1 blockade‐activated DC-CIK cells (hereafter referred to as PD1-T cells), which were manufactured by blocking the PD‐1 epitope in DC-CIK cells with a low-dose of anti-PD-1 antibody (pembrolizumab). 18 , 19 Our previous clinical trials indicated a good safety and efficacy for PD1-T cells in solid tumor. 18 , 19 Based on these findings, we conducted a randomized, multicenter, phase 3 trial to evaluate whether the addition of PD1-T cells to XELOX plus bevacizumab improves efficacy compared to XELOX plus bevacizumab alone in patients with previously untreated mCRC.…”

“… 18 , 19 Our previous clinical trials indicated a good safety and efficacy for PD1-T cells in solid tumor. 18 , 19 Based on these findings, we conducted a randomized, multicenter, phase 3 trial to evaluate whether the addition of PD1-T cells to XELOX plus bevacizumab improves efficacy compared to XELOX plus bevacizumab alone in patients with previously untreated mCRC.…”