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

Abstract

Background: The number of clinical studies evaluating the benefit of cytokine-induced killer cell (CIK) therapy, an adoptive immunotherapy, for colorectal cancer (CRC) are increasing. In many of these trials CIK therapy was co-administered 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. Methods: Prospective and retrospective clinical studies which compared CIK therapy to non-CIK therapy in CRC patients were searched for electronically on MEDLINE, Embase, CNKI 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-analysed using hazard (HR) and relative ratios (RR), and subgroup analyses were performed using Chi-square (Chi2) test and I-square (I2) statistics for study design, disease stage, co-therapy type, and timing of administration. Results: In total, 70 studies involving 6,743 patients were analysed. CIK therapy was favoured over non-CIK therapy for OS (HR=0.59, 95% CI: 0.53-0.65), PFS (HR=0.55, 95% CI: 0.47-0.63), and ORR (RR=0.65, 95% CI: 0.57-0.74) without increasing toxicity (HR=0.59, 95% CI 0.16-2.25). Subgroup analyses on OS and PFS by study design (randomised versus non-randomised study design), disease stage (Stage I-III versus Stage IV), co-treatment with dendritic cells (CIK versus DC-CIK therapy), or timing of therapy administration (concurrent versus sequential with co-administered anti-cancer therapy) also showed that the clinical benefit of CIK therapy was robust in any subgroup analysis. Furthermore, co-treatment with dendritic cells did not improve clinical outcomes over CIK therapy alone. Conclusions: Compared with standard therapy, patients who received additional CIK cell therapy had favourable 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.…”

“…For example, in four studies reporting CIK cell therapy for CRLM each used a different production protocol [ 14 , 28 , 37 , 38 ]. Media used included serum free media or media supplemented with human serum or 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 ].…”

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

“…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].…”