Low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors: a phase I/II report

Abstract

Aberrant DNA methylation is one of the main drivers of tumor initiation and progression. The reversibility of methylation modulation makes it an attractive target for novel anticancer therapies. Clinical studies have demonstrated that high-dose decitabine, a hypomethylating agent, results in some clinical benefits in patients with refractory advanced tumors; however, they are extremely toxic. Low doses of decitabine minimize toxicity while potentially improving the targeted effects of DNA hypomethylation. Based on these mechanisms, low-dose decitabine combined with chemoimmunotherapy may be a new treatment option for patients with refractory advanced tumors. We proposed the regimen of low-dose decitabine-based chemoimmunotherapy for patients with refractory advanced solid tumors. A favorable adverse event profile was observed in our trial that was highlighted by the finding that most of these adverse events were grades 1-2. Besides, the activity of our cohort was optimistic and the clinical benefit rate was up to 60%, and the median PFS was prolonged compared with PFS to previous treatment. We also identified a significant correlation between the PFS to previous treatment and clinical response. The low-dose DAC decitabine-based chemoimmunotherapy might be a promising protocol for improving the specificity and efficiency of patients with refractory advanced solid tumors. This trial is registered in the ClinicalTrials.gov database (identifier NCT01799083).

Figures

Figure 1

Study design. Chemo: chemotherapy; CIK: cytokine induced killer cells.

Figure 2

Trial profile. (∗) Reasons for not meeting the inclusion criteria: patient had a massive hemorrhage (n = 1). CIK: cytokine induced killer cells. DAC + Chemo: DAC combined with chemotherapy group; DAC + CIK: DAC combined with CIK group.

Figure 3

CT image for UPN 20 exhibited a partial response. A CT image showing the specific characteristics of the response of lung lesion following four cycles of decitabine treatment, assessing by the Response Evaluation Criteria in Solid Tumors (RECIST). The red arrows indicate the areas of measurable disease.

Figure 4

Swim plot showing the increase in progression-free survival (PFS) compared with the patients' previous therapies. The bars represent the progression-free survivals (PFSs) of the DAC (a) and DAC combined with chemo (b) or CIK (c) versus the PFSs following the patients' previous therapies. Four patients had died by the first assessment (due to disease progression) and were therefore not evaluated. ∗ The patients' progression-free survivals (PFSs) were significantly prolonged compared with those of previous therapies; P value <0.05 was considered significant. CIK: cytokine induced killer cells. # Patients with disease progression. ▲ Patients who died.

Figure 5

In vivo and in vitro biological activities of decitabine (DAC) were shown in human hepatocellular carcinoma HepG2 cell line and peripheral blood mononuclear cells (PBMCs). (a) Quantitative RT-PCR analyses of the mRNA levels of RASSF1A, MAGEA-3, MAGEA-1, p16, p15, and BRCA1 expression on human hepatocellular carcinoma HepG2 cell line; the cell lines were treated with 10 nM DAC for 72 h before collecting mRNA for analysis. Compared to untreated control, the mRNA expression levels of MAGEA-3, MAGEA-1, p16, and p15 were augmented significantly in treated cell line. (b, c) Quantitative RT-PCR analyses of the mRNA levels of MAGEA-3, MAGEA-1, p16, and p15 expression in peripheral blood mononuclear cells (PBMCs) from patients who exhibited prolonged disease stabilization following low-dose DAC treatment for the first cycle. Progressive increases in the mRNA expressions of MAGEA-3, MAGEA-1, p16, and p15 were observed in patient UNP 25; in contrast, the p16 and p15 mRNA expressions were reduced in patient UNP 14. (d) Methylation-specific PCR analyses of the changes in MAGEA-1 promoter methylation levels in peripheral blood mononuclear cells (PBMCs) collected from patients UNP 25 and UNP 14, during the first treatment cycle. The levels of MAGEA-1 promoter methylation of patients UNP 14 and UNP 25 were reduced and the levels of MAGEA-1 promoter unmethylation were increased at the same time. M: methylation; U: unmethylation. *P < 0.05, for the significance of the gene expressions differences between the DAC treatment sample and the pre-DAC sample. Error bars represent standard deviation of the measurements.