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 Table of Contents  
Year : 2019  |  Volume : 5  |  Issue : 4  |  Page : 72-76

Progress in clinical follow-up study of dendritic cells combined with cytokine-induced killer for stomach cancer

Lanzhou University Second Hospital; Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, Gansu, People's Republic of China

Date of Submission02-Nov-2019
Date of Acceptance06-Dec-2019
Date of Web Publication26-Dec-2019

Correspondence Address:
Dr. Yumin Li
Lanzhou University Second Hospital, No. 81 of Cuiyingmen, Linxia Road, Chengguan District, Lanzhou 730000
People's Republic of China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_32_19

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Stomach cancer is a common malignant disease and is generally associated with mortality. Immunotherapy, including dendritic cells combined with cytokine-induced killer cells (DC-CIK), poses a significant presence. Follow-up plays a vital role in immunotherapy with stomach cancer by effectively predicting recurrence, promptly diagnosing disease, and early intervening to improve clinical outcome and survival rate. Follow-up guideline takes into these terms which are response evaluation criteria in solid tumors, health-related quality of life, tumor markers, T-lymphocyte subsets, and cytokine on the basis of the National Comprehensive Cancer Network guideline. At the same time, the high-level follow-up team is necessary. Hitherto, there is no specific follow-up guide for immunotherapy. This article reviews the follow-up of DC-CIK with stomach cancer, and it is expected that more researchers focus on this issue to draw up utility guidelines of immunotherapy for stomach cancer.

Keywords: Dendritic cells combined with cytokine-induced killer, follow-up, immunotherapy, stomach cancer

How to cite this article:
Wang L, Wan R, Chen C, Su R, Li Y. Progress in clinical follow-up study of dendritic cells combined with cytokine-induced killer for stomach cancer. Cancer Transl Med 2019;5:72-6

How to cite this URL:
Wang L, Wan R, Chen C, Su R, Li Y. Progress in clinical follow-up study of dendritic cells combined with cytokine-induced killer for stomach cancer. Cancer Transl Med [serial online] 2019 [cited 2021 Jan 17];5:72-6. Available from: http://www.cancertm.com/text.asp?2019/5/4/72/274031

  Introduction Top

Stomach cancer ranks fifth for the number of new global cancer cases, approximately 1.0 million diagnoses are estimated in 2018, contributing about 5.7% of the total cancer incidence burden. Stomach cancer is the third type in terms of the number of deaths, 783,000 deaths occurred, accounting for 8.2% of the cancer deaths.[1] Although signs of progress in surgical techniques, chemotherapeutic regimens, radiations and targeted therapies, clinical outcomes of patients with stomach cancer remain poor. Abundant patients suffer severe side effects and recurrence, even more, the 5-year survival rate is under 5% in advanced unresectable or metastatic disease and of which approximately 80% of patients were diagnosed.[2] Hitherto, biological immunotherapy makes a breakthrough in the aspect of anticancer. As a novel type of immunotherapies, dendritic cells (DCs) combined with cytokine-induced killer cells (CIKs) generate remarkable killing effects on tumor cells.[3],[4] DCs are professional antigen-presenting cells, which present tumor antigens to T-lymphocytes and induce antitumor immune responses. DCs function as stimulators of effective T-cells through the promotion of the generation of helper and cytotoxic T-cells.[5],[6],[7] Since CIK traits as recognizing cancer cells, against tumor activity of T-lymphocytes and the non-MHC-restricted tumor-killing ability of natural killer cells, it performs far better in proliferation rate, antitumor activity, and antitumor spectrum.[8],[9],[10],[11] DC-CIK stimulates the immune response of the body to fight tumor cells by the retransformation effect of the cells which depends on the high killing activity of effector cells and the autologous immune system. The virtue of DC-CIK treatment is that the high proliferation rate and cytotoxic activity against adequate cancer types, the simple and mild culture conditions, little adverse reactions, and satisfactory patient compliance.[12],[13],[14] DC-CIK has been widely used to treat stomach cancer as a clinical trial (Flowchart for the treatment of DC-CIK is in [Figure 1]) that brings forth enhanced immune function, improved survival, and better clinical responses for patients with stomach cancer.[15]
Figure 1: Flowchart for the treatment of dendritic cells combined with cytokine-induced killer

Click here to view

Follow-up plays a crucial role in clinical trials. The guidelines of the National Comprehensive Cancer Network (NCCN) for stomach cancer cover the follow-up items.[16] This review summarizes follow-up clinical results obtained so far with DC-CIK treatment for stomach cancer and discusses the novel strategies to improve the quality of clinical trials.

  Immune Response Evaluation Criteria in Solid Tumours Top

Changes in tumor burden play a critical role in evaluating cancer therapeutic.[17] The response evaluation criteria in solid tumors (RECIST),[18] which are conventional radiological response criteria, have been used in clinical trials of DC-CIK for stomach cancer.[19],[20],[21],[22] As there are differences in response mechanisms of tumors treatment between immunotherapies and chemotherapeutic agents or targeted therapies, precision estimation of the response is a big tissue.[23] For example, pseudoprogression (PsPD) could induce in misinterpretation of the patient's status and generate suboptimal clinical decisions. Then, PsPD is immune-related response patterns, such as an initial increase in tumor burden or the appearance of new lesions. Whether new lesion or tumor burden was measured, and how many were captured.[24] Taking this into account, the RECIST working group published a proposition of new criteria called iRECIS (immune) that is a standard approach, which is appropriate for solid tumor measurements and objective change of tumor size in immunotherapy trials. In addition, it defines the minimum data points required from future trials and those currently in development to facilitate the compilation of a data library to use to later validate immune RECIST (iRECIST).[25] In conclusion, iRECIST should be recommended in clinical trials thereafter.

  Health-Related Quality of Life Top

Health-related quality of life (HRQOL) is vital for health-care professionals, involving in the oncology setting. The United States Food and Drug Administration recognizes the benefits of HRQOL as a basis for approval of new anticancer drugs, and HRQOL was included as the primary endpoint of many international research groups.[26] The four components of physical, psychological/emotional, social, and occupational well-being make up HRQOL, which is a subjective concept.[27],[28] Currently, a lot of questionnaires are used to measure HRQOL among oncological patients. Existing DC-CIK clinical trial refers to KPS,[20],[29],[30],[31],[32],[33] which has own limitations while assessing patient prognosis at the end of life. For instance, limited physical functioning was focalized among cancer patients. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the Functional Assessment of Cancer Therapy-General (FACT-G) have a wide range of applications in QOL assessment questionnaires for cancer patients. Quality of Life Questionnaire-QLQ-STO22 and FACT-Gastric (FACT-Ga) are stomach cancer-specific questionnaires. The QLQ-STO22 consists of 52 items instrument, emphasizing the functional and physical concerns of patients, whereas the FACT-Ga comprises 47 items, underlining social and emotional issues to some extent.[34] HQL may be used to monitor morbidity and mortality and provide treatment decisions.[35] On the basis of the specific patient characteristics and objects of the study, the optimal questionnaire should be established. Hypothetically, we may firmly arrive at an indisputable specific questionnaire for stomach cancer which can provide essential information regarding patients' QOL and the efficacy of immunotherapy, including DC-CIK.

  Tumor Markers Top

Carbohydrate antigen (CA) 724, cancer antigen embryonic antigen (CEA), CA199, alpha-fetoprotein (AFP), and CA125 are widely detected in clinical practice of stomach cancer.[36],[37] CA724 is the most effective marker for detecting advanced stomach cancer and has the highest positive rate in nodal involvement or serosal invasion patients among these tumor markers.[38] CEA is strongly correlated with the tumor, node, and metastases stage. The CEA is connected with tumor size, vascular involvement, serosal invasion, lymph node, and hepatic metastases in cancer patients. CA199 was frequently reported to be connected with nodal involvement among various clinicopathological factors, such as tumor depth, nodal involvement, peritoneal metastases, and stages.[39] The combinations of CEA, CA199, and CA724 are the most effective ways before surgery or chemotherapy, which may be available to detect recurrence or evaluation of the response. AFP is of value with detecting and predicting liver metastases.[40] CA125 is serviceable for monitoring peritoneal metastases.[38] Nevertheless, minority clinical trials have not detected some of the above-mentioned serum tumor markers.[19],[32],[41],[42],[43] Although the five serum markers are insensitive for screening early stomach cancer, they are useful in monitoring after treatment for stomach cancer such as detecting recurrence and distant metastasis and predicting survival.[44] The guideline, which is the clinical utility of serum markers for stomach cancer patients during treatment, should be established through a phase III prospective randomized trial for DC-CIK.

  T-Lymphocyte Subsets and Cytokine Top

The immune function and T-lymphocyte subsets percentage in the peripheral blood of cancer patients is distinctive from noncancer patients. CD3+ cells reflect the overall cell immune state of organisms and are the sum of the number of CD4+ and CD8+ cells.[45] CD4+ T-cells, namely helper T-cells, including in Th1-cells and Th2-cells, which effect by recruiting CD8+ T-cells and activating macrophages.[46] Th1 cells build up cytotoxicity of killer cells and induce delayed-type hypersensitivity, whereas Th2-cells lead to the immunity escape of tumor cells. The counterbalance between Th1- and Th2-cells matters in immunotherapy.[47] It is observed that the absolute number and percentage of CD3+ and CD3+ CD4+ T-cells in peripheral blood of the normal healthy controls were obviously high than the advanced stomach cancer patients.[48],[49] CD3+CD8+ cytotoxic T-lymphocytes (CTLs) take effect in immune defense. CD3+CD4+ T-cells act a part in anti-tumor immune responses through promoting the proliferation of CD3+CD8 + CTLs. Interaction between CD4+ and CD8+ T-cells affects cytotoxicity against tumors.[50],[51] Survival rates of stage III stomach cancer patients are positively correlated with percentages of CD4+ lymphocytes and the absolute number of CD8+ cells, controversially, lower percentages of CD8+ lymphocytes are associated with longer survival in another article.[52],[53] Regulatory T-cells (Tregs), defined as CD3+CD4+CD25+/CD4+CD25+Foxp3+ T-cells, work by repressing CD3+CD8+ T-cell action and is relevant to poor prognosis in cancers.[54],[55] CIK refers to two main heterogeneous cell subsets, CD3+/CD56 + and CD3+/CD58+. CIK could direct contact and secrete cytokines, such as interleukin-2 (IL-2), interferon-γ (IFN-γ), and tumor necrosis factor (TNF), and then induce apoptosis and inhibit the proliferation of tumor cells.[56],[57] When co-cultured with CIK and DC, the expression of cytokines such as IL-2, IFN-r, TNF, IL-12, and the rates of the main effector cells were increased, which strengthen the cytotoxicity of CIK.[6] Almost all clinical trials of DC-CIK have measured T-lymphocyte subsets and cytokine levels to assess immune status.[18],[20],[21],[30],[42],[58],[59],[60],[61],[62] It is reported that indicators of reactive immune status, for instance, the percentage of lymphocyte subsets (CD3+, CD4 + and CD3 − CD56+, CD3 + CD56+), the levels of IL-12 and IFN-γ, were apparently enhanced by the CIK/DC-CIK therapy.[15] There is no doubt that we may firmly arrive at an indisputable guideline about T-lymphocyte subsets and cytokine and implemented in clinical studies for DC-CIK.

  Discussion Top

The therapeutic mechanism of stomach cancer has changed when immunotherapy such as PD-1 and CAR-T have been applied in clinical treatment, new examining item, involving in positron emission tomography–computed tomography (CT) and CT colonography, have been a prognostic factor in the clinical treatment of breast cancer.[63] The current guidelines of follow-up are deficient. To ensure consistent design and data collection and ultimate validation of the guideline, the new specific guideline of stomach cancer for immunotherapy (DC-CIK) should be established where optimize items mentioned in this article and based on NCCN guidelines for stomach cancer. To performance bias of follow-up, excellent follow-up team and professional management are irreplaceable. First, the follow-up team consists of doctors, nurses, epidemiologists, statistics, psychologists, and nutritionists. All members of the follow-up team are informed that humanistic care matters and they should not withdraw optionally. The members should be rigorously trained in related-study knowledge and communication skills. Nurses take charge of keeping in contact with doctors and patients, fixing the time, filling out and collecting booklets, addressing the problems, and reflecting on the manager. Even if patients change hospitals, the follow-up should be insisted on by contacting the staff of the hospital. Epidemiologists and statisticians are in charge of statistical data and deal with problems in the study. NCCN guideline refers to vitamin and Iron; nutritionists give dietary instruction for participants. Cancer is a risk factor for developing emotional disturbances, especially depression and risk of suicide among cancer patients compared with the general population.[64],[65] Psychologists are responsible for psychological therapy. The leader of the follow-up is made arrangements and responsible for coordinating with all things. Second, the pattern of follow-up needs to integrate outpatient, telephone, network, and home follow-up. By home follow-up, investigating the needs of individuals and families to solve the difficulties during the treatment. Explaining disease knowledge and answering questions by network follow-up. In addition, the outpatient follow-up should give first to place. Doctors in charge who are more trusted by patients and communication are more effective are responsible for carrying out content and filling out the booklet in the outpatient department. Third, standardized management is also important. IT is needed that setting up electronic archives, draft booklet which is owned by doctors and patients, respectively. Taking booklets with patients, they can immediately fill in information such as side effects, as well as stimulate a sense of participation to reduce the expulsion rate.

In sum, it is irreplaceable to design and implement a follow-up system for improving the validity and safety of immunotherapy (DC-CIK) with stomach cancer patients.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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Tumor Markers
T-Lymphocyte Sub...
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