A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma
With a resistance to conventional chemotherapy and radiotherapy, hepatocellular carcinoma has a high recurrence rate after radical resection. Adjuvant immunotherapy is a promising treatment for hepatocellular carcinoma.
Aim
To evaluate the effect of adjuvant immunotherapy with cytokine-induced killer cells on the prognosis of hepatocellular carcinoma after radical resection.
Patients and methods
From January 2000 to January 2002, we collected 127 patients that met the selection criteria and randomly divided them into 3 groups. After radical resection of the tumor, immunotherapy with cytokine-induced killer cells was performed for 3 courses in 41 patients (CIK-I group) and 6 courses in 43 patients (CIK-II group). The other 43 patients received no postoperative adjuvant therapy (the control group). The 1-, 3-, and 5-year disease free survival rates and the overall survival were compared among the 3 groups.
Results
The log-rank test showed that the disease-free survival rates were significantly higher in CIK-I group (p = 0.001) and CIK-II group (p = 0.004) than in the control group. No statistical significance was found between CIK-I group and CIK-II group (p = 0.345). Cox regression suggested that treatment modality was a risk factor for recurrence. No statistical significance was found in the overall survival among the three groups.
Conclusions
Postoperative immunotherapy with cytokine-induced killer cells may prevent recurrence/metastasis after radical resection of hepatocellular carcinoma. However, it cannot improve the overall survival.
Introduction
Through out the world, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death [1], [2]. HCC is particularly prevalent in China because of the high infection rate of hepatitis B. Meanwhile, its incidence is also increasing in the Western world [3]. Despite remarkable improvements in therapeutic procedures of HCC in the past decades, liver resection and liver transplantation are still considered as the potentially curative treatments for HCC. Due to the limitations of liver transplantation (graft availability, selection criteria, and cost), a large number of HCC patients in China were treated with liver resection. However, postoperative recurrence is frequently observed. Therefore, the prevention of recurrence constitutes one of the most challenging issues in improving the efficacy of surgery. As is well known, HCC is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy [4]. We hypothesized that adjuvant immunotherapy might benefit patients who underwent resection of HCC. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes (CTL). They are non-MHC-restricted and are generated by incubation of peripheral blood lymphocytes with anti-CD3 monoclonal antibody, IL-2, IL-1 and interferon gamma (IFN-γ) [5]. CIK cells represent strong anti-tumor cytotoxicity in vitro and in vivo [6]. These cells have demonstrated higher proliferative and cytolytic activities in comparison with the lymphokine activated killer cells (LAK cells) that are essentially activated natural killer (NK) cells. Accordingly, we conducted a randomized controlled trial to evaluate the efficacy of adjuvant immunotherapy with CIK cells after radical resection of HCC.
Section snippets
Patients
According to the selection criteria (Table 1), 127 HCC patients who underwent curative hepatic resection in Cancer Hospital of Tianjin Medical University between January 2000 and January 2002 were enrolled in this trial. The nature of this study was fully explained to these patients, and informed consent was obtained from all of them. The study protocol conformed to the principles of Declaration of Helsinki (1983) and was approved by Tianjin Anti-Cancer Association.
Study design
The aim of this trial was to
Side effects
Due to side effects, three patients in CIK-I group and two patients in CIK-II group failed to fulfil the CIK immunotherapy. Persistent febrility was the only side effect observed in the above five patients. However, the temperature of all these patients was lower than 38.5 °C. During the 5–7 years’ follow-up, no long-dated side effects had been observed in all patients of the CIK-I and CIK-II groups.
In spite of the great improvement in hepatic operation technique and early diagnosis of HCC, the prognosis of HCC is still poor because of a high incidence of postoperative recurrence and metastasis. After curative resection or transplantation, tumor recurrence rate can be as high as 25% per year [7]. Although some centers have reported excellent long-term results, survival after hepatic resection or transplantation is as low as 50% at 3 years and 20–30% at 5 years [8], [9]. Systemic and
Conclusion
Postoperative adjuvant immunotherapy with CIK cells may be a valuable therapeutic strategy for HCC patients in preventing recurrence and metastasis, although it has not approved effective on the overall survival in this trial.
Practice points
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Hepatocellular carcinoma is one of the most common cancers and the patient survival is poor because of a high recurrence rate after resection.
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In recent years, immunotherapy has become an important treatment modality for HCC, and some studies have shown that
Conflict of interest
None.
Acknowledgement
We thank Epidemiology Institute, Cancer Hospital of Tianjin Medical University for statistical analyses and graphical development.
The translation of natural killer (NK) cells to the treatment of malignant disease has made significant progress in the last few decades. With a variety of available sources and improvements in both in vitro and in vivo NK cell expansion, the NK cell immunotherapy platform has come into its own. The enormous effort continues to further optimize this platform, including ways to enhance NK cell persistence, trafficking to the tumor microenvironment, and cytotoxicity. As this effort bears fruit, it is translated into a plethora of clinical trials in patients with advanced malignancies. The adoptive transfer of NK cells, either as a standalone therapy or in combination with other immunotherapies, has been applied for the treatment of both liquid and solid tumors, with numerous early-phase trials showing promising results. This review aims to summarize the key advantages of NK cell immunotherapy, highlight several of the current approaches being taken for its optimization, and give an overview of the landscape of clinical trials translating this platform into clinic.
2021, Hepatobiliary and Pancreatic Diseases International
Treatment of hepatocellular carcinoma (HCC) is challenging as most patients are diagnosed at advanced stage with underlying chronic liver conditions. Conventional systemic chemotherapy has failed in HCC, and the clinical efficacy of FDA-approved molecular targeted agents such as sorafenib and lenvatinib remains unsatisfactory.
Literature search was conducted in PubMed for relevant articles published before January 2021. The search aimed to identify recent developments in immune-based treatment approaches for HCC. Information of clinical trials was obtained from https://clinicaltrials.gov/.
Two immune checkpoint inhibitors (ICIs), nivolumab and pembrolizumab were approved as monotherapies, which has revolutionized HCC treatment. Besides, combination ICIs have also got accelerated FDA approval recently. Immune-based therapies have challenged targeted drugs owing to their safety, tolerability, and survival benefits. In addition to the significant success in ICIs, other immunotherapeutic strategies such as cancer vaccine, chimeric antigen receptor T-cells, natural killer cells, cytokines, and combination therapy, have also shown promising outcomes in clinical trials. Various diagnostic and prognostic biomarkers have been identified which can help in clinical decision making when starting treatment with ICIs.
Immunotherapy has emerged as one of the mainstream treatment modalities for advanced HCC in recent years. However, challenges such as low response rate and acquired resistance in previously respondent patients still exist. Further research is needed to understand the unique resistance mechanism to immunotherapy and to discover more predictive biomarkers to guide clinical decision making.
Hepatocellular carcinoma (HCC) is a lethal malignancy with poor prognosis. More than 80% of patients are diagnosed at an advanced stage, and most patients with HCC also have liver cirrhosis that complicates cancer management. No targeted treatment options currently exist outside genomics-based clinical trials. Multiple tyrosine kinase inhibitors (mTKIs) such as sorafenib, lenvatinib, cabozantinib, and regorafenib have been used to treat advanced hepatocellular carcinoma (aHCC). Immune checkpoint inhibitors including nivolumab and pembrolizumab have shown survival benefit. More recently, atezolizumab in combination with bevacizumab resulted in improved overall survival and progression-free survival, compared with sorafenib in patients with aHCC in the first-line setting. The combination of nivolumab with ipilimumab as an alternative in the treatment of patients treated with sorafenib has inspired various combination studies of immune checkpoint inhibitors. Currently, ongoing studies of systemic therapy consist of various immune-based combination therapies. Finally, there is no established adjuvant and neoadjuvant therapy although a few early phase studies show promising results. In this chapter, we summarize current approaches of systemic treatment in patients with liver cancer.