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

After 2 cycles of infusion

After 2 cycles of infusion

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Summary

In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and dendritic cells-co-cultured cytokine-induced killer cells in patients with advanced renal cell carcinoma. The combination therapy was active and well tolerated for treatment of advanced RCC.

Patients characteristics

43 patients with irresectable or metastatic renal cell carcinoma (RCC) were 18 years of age or older with histologically or cytologically confirmed metastatic RCC and at least one measurable disease [according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)]. Patients who had not have received any previous systemic anticancer therapy, or those who had received one treatment with sorafenib, pazopanib, sunitinib, or other VEGFR-targeting tyrosine kinase inhibitor (other than axitinib) for advanced disease and had radiographic progression. Eastern Cooperative Oncology Group performance status of 0– 2; a life expectancy of greater than 12weeks; adequate renal, hepatic and hematological organ function; and no HIV infection or chronic active hepatitis.

Methodology

Vaccine preparation
Peripheral blood mononuclear cells were separated using Ficoll-Hypaque density centrifugation and cultured in X- VIVO 15 medium for 1 hour. The suspended cells were then collected to induce CIK cells using 1000 U mL-1 recombinant human IFN-c for the first 24 hours followed by stimulation with 100 ng mL-1 mouse anti-human CD3 monoclonal antibody, 1000 U mL-1 IL-2, and 100 U mL-1 IL- 1a. The adherent cells were cultured using DC medium (X-VIVO 15 medium, supplemented with 1000 U mL-1 GM-CSF and 30 ng mL-1 IL-4) to induce DCs. After matured with 10 ng mL-1 of TNF- a on the sixth day, DCs were mixed with the CIK cells at a ratio of 1:20 and cultured in fresh medium containing 1000 U mL-1 IL-2 for another 7 days to induce DC-CIK cells. Secondly, on day 14, the DC-CIK cells were harvested and analysed for number, viability, and phenotype. Before the DC-CIK cells were transferred to patients, they were incubated with pembrolizumab (1 μg 10-6 cell) for 30– 40 min at 37°C to induce pembrolizumab-activated DC-CIK cells.

Treatment

The enrolled patients received axitinib and pembrolizumab- activated autologous DC-CIK cell immunotherapy until disease progression. Axitinib was given orally at a starting dose of 5 mg twice daily. The dose could be increased to 7 mg, then 10 mg, twice daily if there were no adverse reactions above grade 2 of Common Terminology Criteria for Adverse Events. The axitinib dose could be reduced to 3 mg, then 2 mg, twice daily to manage toxic side-effects.
The pembrolizumab-activated autologous DC-CIK cells were infused intravenously. In general, patients received at least 4 cycles of cell infusion with a 1-week interval between each cycle. Then, another 4 cycles of treatment would be given at 2-week intervals. Patients who achieved good disease control were eligible for cell maintenance treatment once every month. Patients received a median of 1.2×1010 (range, 0.8×1010 to 1.5×1010) pembrolizumab-activated autologous DC-CIK cells per cycle.

Results

Efficacy
At the date of the analysis (the cut-off date), the median follow-up for the 43 patients in this study was 23.6 months. Twenty-six (60.5%) patients had disease progression (PD), and 2 (4.7%) patients had died from disease progression.
In the treatment- naive and VEGFR-targeting TKI-pretreated subpopulations, 11 and 15 PFS events were recorded, respectively. Median PFS was 14.7 months (95%) in the overall study population. The percentages of patients without disease progression at 6 and 12 months were 72.1% and 62.1%, respectively.
Median PFS was 18.2 and 14.4 months for the patients untreated versus previously treated with targeted therapy, respectively. PFS rate at 12 months for patients untreated versus previously treated with targeted therapy were 71.6% and 52.4%, respectively. Median PFS in ccRCC and pRCC were 17.3 and 14.4 months, respectively.
The observed objective response rate (ORR) in the entire population was 25.6% (including 1 complete response (CR) and 10 partial responses (PR), with a median duration of response of 18.2 months. Twenty- one of 43 patients (48.8%) had stable disease (SD). Patients in the treatment-naive subpopulations had an ORR of 31.8% which was not significantly improved than that in the VEGFR-targeting TKI- pretreated subpopulation (19%).
Safety
Most patients only had mild (grade 1–2) adverse events similar to those previously reported with single- agent axitinib. Diarrhoea (48.8%), palmar-plantar erythrodysesthesia (37.2%), hypertension (30.2%), and proteinuria (25.6%) were the most common adverse events (AEs). The most common grade 3–4 AEs were hypertension (11.6%), palmar-plantar erythrodysesthesia (7.0%), diarrhoea (4.7%), and proteinuria (4.7%). Immune-related AEs as potential toxicities of interest were also recorded during the administration of autologous pembrolizumab-activated DC-CIK cells. In this study, only five (11.6%) patients developed grade 1 chill and fever, which were related to the infusion of pembrolizumab-activated DC-CIK cells and recovered spontaneously without any medical treatment. No immune-related serious adverse events such as pneumonitis, colitis, hepatitis, nephritis, and myocarditis appeared in any of the patients. No patients died for AEs, and no treatment was discontinued in any patients because of treatment-related AEs.

Conclusion

This study demonstrated that the combination of axitinib plus pembrolizumab-activated autologous DC- CIK cells contributed to encouraging clinical outcomes in patients with advanced RCC who treatment- naive or targeted agents were- pretreated. Although overall survival data are not mature at this time, survival analyses will help to elucidate the utility of this combination therapy as a first- or second-line therapy for patient with advanced RCC. This combination therapy was well tolerated and manageable.

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Scientific article publishing date 2/1/2021

Immucura identifier BSC21_293EN

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