Advertisement

Adjuvant cytokine-induced killer cell immunotherapy improves long-term survival in patients with stage I–II non-small cell lung cancer after curative surgery

Published:November 12, 2022DOI:https://doi.org/10.1016/j.jcyt.2022.10.008

      Abstract

      Background aims

      Non-small cell lung cancer (NSCLC) remains the most common cancer worldwide, with an annual incidence of around 1.3 million. Surgery represents the standard treatment in early-stage NSCLC when feasible. However, because of cancer recurrence, only approximately 53% of patients with stage I and II NSCLC survive 5 years after radical surgery. The authors performed a retrospective study to investigate the impact of cytokine-induced killer (CIK) cell immunotherapy on the long-term survival of patients with stage I–II NSCLC after curative resection.

      Methods

      Fifty-seven patients with NSCLC were included in the study, with 41 and 16 in the control and CIK groups, respectively. Clinical characteristics were compared using a t-test and χ2 test. Survival analysis of patients with NSCLC was performed using the Kaplan–Meier method. The phenotypes and anti-tumor functions of CIK cells were evaluated by flow cytometry.

      Results

      Patients in the CIK group exhibited significantly longer overall survival (OS) and better disease-free survival (DFS) than those in the control group. Subgroup analysis indicated that patients with a higher risk of recurrence benefited more from CIK treatment and attained longer OS and DFS compared with those in the control group. No severe adverse events related to CIK treatment occurred. CIK cells contained a higher proportion of CD3+CD56+ natural killer (NK) T cells and CD3+ and CD8+ T cells and a lower proportion of CD3CD56+ NK cells compared with peripheral blood mononuclear cells. CIK cells exhibited potent tumor-killing ability, with longer contact times with tumor cells and a greater number of cells exposed to tumor cells.

      Conclusions

      The authors’ data suggest that adjuvant CIK cell therapy is a safe and effective therapeutic strategy for improving OS and DFS in patients with stage I–II NSCLC after curative resection.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Cheng Y.
        • Zhang T.
        • Xu Q.
        Therapeutic advances in non-small cell lung cancer: focus on clinical development of targeted therapy and immunotherapy.
        MedComm. 2021; 2: 692-729
        • Bille A.
        • et al.
        Incidence of occult pN2 disease following resection and mediastinal lymph node dissection in clinical stage I lung cancer patients.
        European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery. 2017; 51: 674-679
        • Deboever N.
        • et al.
        Current Surgical Indications for Non-Small-Cell Lung Cancer.
        Cancers. 2022; 14: 1263
        • Yeong J.
        • et al.
        High Densities of Tumor-Associated Plasma Cells Predict Improved Prognosis in Triple Negative Breast Cancer.
        Frontiers in immunology. 2018; 9: 1209
        • Zhang L.
        • et al.
        Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
        N Engl J Med. 2003; 348: 203-213
        • Whiteside T.L.
        Tumor-Infiltrating Lymphocytes and Their Role in Solid Tumor Progression.
        Exp Suppl. 2022; 113: 89-106
        • Zhang D.
        • et al.
        Prognostic Impact of Tumor-Infiltrating Lymphocytes in Laryngeal Squamous Cell Carcinoma Patients.
        Laryngoscope. 2021; 131: E1249-E1255
        • Zhou C.
        • et al.
        Monitoring Pre- and Post-Operative Immune Alterations in Patients With Locoregional Colorectal Cancer Who Underwent Laparoscopy by Single-Cell Mass Cytometry.
        Front Immunol. 2022; 13807539
        • Seth R.
        • et al.
        Surgical stress promotes the development of cancer metastases by a coagulation-dependent mechanism involving natural killer cells in a murine model.
        Ann Surg. 2013; 258: 158-168
        • Pretzsch E.
        • et al.
        Operative Trauma and Blood Loss—Impact on Tumor Growth and Recurrence.
        Shock. 2021; 55: 455-464
        • Alieva M.
        • van Rheenen J.
        • Broekman M.L.D.
        Potential impact of invasive surgical procedures on primary tumor growth and metastasis.
        Clinical & experimental metastasis. 2018; 35: 319-331
        • Market M.
        • Tennakoon G.
        • Auer R.C.
        Postoperative Natural Killer Cell Dysfunction: The Prime Suspect in the Case of Metastasis Following Curative Cancer Surgery.
        International journal of molecular sciences. 2021; 22: 11378
        • Powles T.
        • et al.
        ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.
        Nature. 2021; 595: 432-437
        • Qian H.
        • et al.
        Progress and application of circulating tumor cells in non-small cell lung cancer.
        Mol Ther Oncolytics. 2021; 22: 72-84
        • Lazzari C.
        • et al.
        Angiogenesis inhibition in lung cancer: emerging novel strategies.
        Curr Opin Oncol. 2022; 34: 107-114
        • Chen Y.
        • et al.
        Quantification of STAT3 and VEGF expression for molecular diagnosis of lymph node metastasis in breast cancer.
        Medicine. 2017; 96: e8488
        • Bakos O.
        • et al.
        Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity.
        Journal for immunotherapy of cancer. 2018; 6: 86
        • Si X.
        • et al.
        In-Situ-Sprayed Dual-Functional Immunotherapeutic Gel for Colorectal Cancer Postsurgical Treatment.
        Adv Healthc Mater. 2021; 10e2100862
        • Schmidt-Wolf I.G.
        • et al.
        Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells.
        Exp Hematol. 1993; 21: 1673-1679
        • Schmidt-Wolf I.G.
        • et al.
        Use of a SCID mouse/human lymphoma model to evaluate cytokine-induced killer cells with potent antitumor cell activity.
        The Journal of experimental medicine. 1991; 174: 139-149
        • Li R.
        • et al.
        Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study.
        Cancer Immunol Immunother. 2012; 61: 2125-2133
        • Huang J.
        • et al.
        Chemotherapy in combination with cytokine-induced killer cell transfusion: An effective therapeutic option for patients with extensive stage small cell lung cancer.
        Int Immunopharmacol. 2017; 46: 170-177
        • Pan K.
        • et al.
        Clinical activity of adjuvant cytokine-induced killer cell immunotherapy in patients with post-mastectomy triple-negative breast cancer.
        Clin Cancer Res. 2014; 20: 3003-3011
        • Zhao X.
        • et al.
        Cytokine induced killer cell-based immunotherapies in patients with different stages of renal cell carcinoma.
        Cancer Lett. 2015; 362: 192-198
        • Liu Y.
        • et al.
        Long-term clinical efficacy of cytokine-induced killer cell-based immunotherapy in early-stage esophageal squamous cell carcinoma.
        Cytotherapy. 2022; 24: 526-533
        • Kuo S.W.
        • et al.
        Prognostic significance of histologic differentiation, carcinoembryonic antigen value, and lymphovascular invasion in stage I non-small cell lung cancer.
        J Thorac Cardiovasc Surg. 2014; 148: 1200-1207.e3
        • Wang Y.
        • et al.
        Risk stratification model for patients with stage I invasive lung adenocarcinoma based on clinical and pathological predictors.
        Transl Lung Cancer Res. 2021; 10: 2205-2217
        • Tsukioka T.
        • et al.
        Tumor Size and N2 Lymph Node Metastasis Are Significant Risk Factors for Early Recurrence in Completely Resected Centrally Located Primary Lung Cancer Patients.
        Anticancer Res. 2021; 41: 2165-2169
        • Dong C.
        Cytokine Regulation and Function in T Cells.
        Annu Rev Immunol. 2021; 39: 51-76
        • Chaft J.E.
        • et al.
        Evolution of systemic therapy for stages I-III non-metastatic non-small-cell lung cancer.
        Nat Rev Clin Oncol. 2021; 18: 547-557
        • Woodard G.A.
        • Jones K.D.
        • Jablons D.M.
        Lung Cancer Staging and Prognosis.
        Cancer Treat Res. 2016; 170: 47-75
        • Kim R.
        Effects of surgery and anesthetic choice on immunosuppression and cancer recurrence.
        J Transl Med. 2018; 16: 8
        • Ananth A.A.
        • et al.
        Surgical Stress Abrogates Pre-Existing Protective T Cell Mediated Anti-Tumor Immunity Leading to Postoperative Cancer Recurrence.
        PLoS One. 2016; 11e0155947
        • Tran T.B.
        • Maker V.K.
        • Maker A.V.
        Impact of Immunotherapy after Resection of Pancreatic Cancer.
        J Am Coll Surg. 2019; 229: 19-27.e1
        • Fujisawa T.
        • Yamaguchi Y.
        Postoperative immunostimulation after complete resection improves survival of patients with stage I nonsmall cell lung carcinoma.
        Cancer. 1996; 78: 1892-1898
        • Gammaitoni L.
        • et al.
        Cytokine-Induced Killer Cells Kill Chemo-surviving Melanoma Cancer Stem Cells.
        Clin Cancer Res. 2017; 23: 2277-2288
        • Jiang N.
        • et al.
        Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study.
        Clin Cancer Res. 2017; 23: 5066-5073
        • Gammaitoni L.
        • et al.
        Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features.
        Clin Cancer Res. 2013; 19: 4347-4358
        • Zhou Y.
        • et al.
        Retrospective analysis of the efficacy of adjuvant CIK cell therapy in epithelial ovarian cancer patients who received postoperative chemotherapy.
        Oncoimmunology. 2019; 8e1528411
        • Cheng H.
        • et al.
        Preliminary Safety and Potential Effect of 6B11-OCIK Adoptive Cell Therapy Against Platinum-Resistant Recurrent or Refractory Ovarian Cancer.
        Frontiers in immunology. 2021; 12707468
        • Wang Z.
        • et al.
        Targeting prostate cancer stem-like cells by an immunotherapeutic platform based on immunogenic peptide-sensitized dendritic cells-cytokine-induced killer cells.
        Stem cell research & therapy. 2020; 11: 123
        • Qin W.
        • et al.
        DC-CIK cells derived from ovarian cancer patient menstrual blood activate the TNFR1-ASK1-AIP1 pathway to kill autologous ovarian cancer stem cells.
        Journal of cellular and molecular medicine. 2018; 22: 3364-3376
        • Donini C.
        • et al.
        Cellular Immunotherapy Targeting Cancer Stem Cells: Preclinical Evidence and Clinical Perspective.
        Cells. 2021; 10: 543
        • Yang T.
        • et al.
        Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system.
        BMC cancer. 2018; 18: 984
        • Zhao Y.
        • et al.
        Combination of DC/CIK adoptive T cell immunotherapy with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients: a prospective patients' preference-based study (PPPS).
        Clin Transl Oncol. 2019; 21: 721-728
        • Zhang Y.
        • et al.
        Adjuvant treatment for triple-negative breast cancer: a retrospective study of immunotherapy with autologous cytokine-induced killer cells in 294 patients.
        Cancer Biol Med. 2019; 16: 350-360