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).

Phase Ib/II study of safety and efficacy of low‐dose decitabine‐primed chemoimmunotherapy in patients with drug‐resistant relapsed/refractory alimentary tract cancer

“…This clinical trial showed a favorable PFS and clinical response without a significant increase in toxicity. Our previous clinical trials of low‐dose decitabine in other tumors exhibited the similar findings 12, 28…”

“…However, it is becoming increasingly clear that the impact of epigenetics on both the tumor cell and the tumor microenvironment plays a critical role in the development of drug resistance 9, 10, 11. Consistent with this hypothesis, previous laboratory and clinical data suggest that an epigenetic strategy may overcome chemotherapy resistance and mediate a return to a baseline state of treatment susceptibility in various cancers 11, 12, 13, 14, 15. Epigenetic perturbations, particularly hypomethylating agents (HMA), re‐sensitize cancer cells to chemotherapy presumably by resetting the epigenetic infrastructure and altering gene expression in the tumor 16, 17, 18.…”

“…The presence of tumor‐infiltrating T cells correlates with a favorable clinical outcome for cancer,22, 23 and adoptive immunotherapy, such as cytokine‐induced killer (CIK) cells, has shown objective clinical responses in many solid tumors 24, 25. Furthermore, improved clinical activity was observed in cancer patients treated with a combination of epigenetic therapy and adoptive immunotherapy,12, 26 and HMA may play an immune stimulatory role in cancer therapy by sensitizing patients to immune responses 21, 27. Based on the hypomethylating and immune remodeling effects of decitabine,17, 27 we hypothesized that the use of decitabine to prime the cancers to restore sensitivity to cytotoxic drugs and immunotherapy may be a valuable alternative avenue for the clinical efficacy of drug‐resistant relapsed/refractory (R/R) AT cancers.…”

“…Because the safety and efficacy of low‐dose decitabine as either monotherapy or as a drug combination with current standard therapies in patients with various solid tumors has already been shown,12, 28 our phase Ib/II study (http://ClinicalTrials.gov identifier: NCT01799083) was designed to develop a new regimen based on the epigenetic reversion of drug resistance and immunotherapy. In our study, we report the safety, tolerability and efficacy of a combined therapy of low‐dose decitabine plus the re‐administration of previously ineffective, corresponding first‐line chemotherapy and CIK cell treatment to patients, diagnosed within 6 months of their original first‐line therapy, with advanced stage, documented relapsed or refractory AT cancers.…”

Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

“…Nevertheless, they have been recognized as having lower toxicity compared to traditional chemotherapy. In fact, low-dose treatment of Aza-dC in patients with MDS [108] and solid tumors [109] resulted in complete response of the patients. Thus using low-dose DNA methylation inhibitors may provide a safe therapeutic choice [65] especially for elderly patients [107,110] .…”