Use of cytokine-induced killer cell therapy in patients with colorectal cancer: a systematic review and meta-analysis

Abstract

BackgroundThe number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) is increasing. In many of these trials, CIK therapy was coadministered with conventional cancer therapy. The aim of this review is to systematically assess the available literature, in which the majority were only in Chinese, on CIK therapy for the management of CRC using meta-analysis and to identify parameters associated with successful CIK therapy implementation.MethodsProspective and retrospective clinical studies which compared CIK therapy to non-CIK therapy in patients with CRC were searched for electronically on MEDLINE, Embase, China National Knowledge Infrastructure, and Wanfang Data databases. The clinical endpoints of overall survival (OS), progression-free survival (PFS), OS and PFS rates, overall response rate (ORR), and toxicity were meta-analyzed using HR and relative ratio (RR), and subgroup analyses were performed using chi-square (χ2) test and I-squared (I2) statistics for study design, disease stage, cotherapy type, and timing of administration.ResultsIn total, 70 studies involving 6743 patients were analyzed. CIK therapy was favored over non-CIK therapy for OS (HR=0.59, 95% CI: 0.53 to 0.65), PFS (HR=0.55, 95% CI: 0.47 to 0.63), and ORR (RR=0.65, 95% CI: 0.57 to 0.74) without increasing toxicity (HR=0.59, 95% CI: 0.16 to 2.25). Subgroup analyses on OS and PFS by study design (randomized vs non-randomized study design), disease stage (Stage I–III vs Stage IV), cotreatment with dendritic cells (DCs) (CIK vs DC-CIK therapy), or timing of therapy administration (concurrent vs sequential with coadministered anticancer therapy) also showed that the clinical benefit of CIK therapy was robust in any subgroup analysis. Furthermore, cotreatment with DCs did not improve clinical outcomes over CIK therapy alone.ConclusionCompared with standard therapy, patients who received additional CIK cell therapy had favorable outcomes without increased toxicity, warranting further investigation into CIK therapy for the treatment of CRC.

Generation and assessment of cytokine-induced killer cells for the treatment of colorectal cancer liver metastases

“…We recently reported that past clinical studies on CIK cell therapy for CRC were generated from autologous patient-derived PBMCs [11]. Thus, we investigated if PBMCs from CRLM donors have similar capacity to produce CIK cells as healthy donors.…”

“…Media usage ranged from SFMs to serum supplemented media including the use of human serum and FBS ([11] and unpublished observations). While FBS supplementation is still common practice in cell culture for T cell therapies [39], its use increases the risk of xenoimmunisation and zoonotic disease transfer in recipients [16].…”

“…They also mount a type-1 inflammatory response by releasing interleukin (IL)-2, interferon (IFN)-γ and tumour necrosis factor (TNF)-α [7, 9]. Meta-analyses of CRC clinical trials for CIK cell therapy, mostly conducted in China, have shown significant improvement in patient outcomes, including overall and progression-free survival [10, 11].…”

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

“… 14 Among them, CIK/DC-CIK cells have shown promising outcomes in initial clinical trials and demonstrated synergistic anti-tumor effects when coadministered with conventional cancer therapy. 13 , 15 …”

“… 16 , 17 A recent meta-analysis involving 6743 patients from 70 studies also supports this finding, showing that adoptive CIK/DC-CIK cell immunotherapy in combination with standard treatment protocols, particularly chemotherapy, offers remarkable clinical benefits for patients with CRC. 13 However, there remains a lack of randomized, controlled, multicenter clinical studies to further confirm the therapeutic efficacy of adoptive immune cell therapy in CRC.…”