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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 42  |  Issue : 3  |  Page : 134-137

Cellular immunotherapy with immune killer cells for treating a lung cancer patient with liver metastasis


Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan

Date of Submission23-Nov-2020
Date of Decision03-Dec-2020
Date of Acceptance10-Dec-2020
Date of Web Publication14-Jun-2021

Correspondence Address:
Dr. Chih-Feng Chian
114 No. 325, Sec. 2, Cheng-Gong Road, Neihu 114, Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmedsci.jmedsci_384_20

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  Abstract 


Lung cancer has the highest number of deaths globally. About 75% of nonsmall cell lung cancer (NSCLC) cases are diagnosed at an advanced stage. Despite significant therapeutic progress, the prognosis remains poor. For patients who have undergone conventional treatment followed by disease progression, palliative care generally remains the only option. As reported in recent years, cellular immunotherapies play an important role in treating lung cancer and may be an option for terminal-stage disease. We applied a novel management approach with immune killer cells therapy to treat a patient with NSCLC with liver metastases. The carcinoembryonic antigen returned to normal level during the treatment period, and the follow-up abdominal computed tomography at 3 months after completion of the therapy displayed no residual metastatic liver tumors.

Keywords: Immune killer cells therapy, cellular immunotherapy, lung cancer, lung adenocarcinoma, liver metastasis


How to cite this article:
Wang CY, Peng CK, Chian CF. Cellular immunotherapy with immune killer cells for treating a lung cancer patient with liver metastasis. J Med Sci 2022;42:134-7

How to cite this URL:
Wang CY, Peng CK, Chian CF. Cellular immunotherapy with immune killer cells for treating a lung cancer patient with liver metastasis. J Med Sci [serial online] 2022 [cited 2022 Jun 29];42:134-7. Available from: https://www.jmedscindmc.com/text.asp?2022/42/3/134/318372




  Introduction Top


Lung cancer is the most frequent cause of cancer-related death globally,[1] with 1.6 million deaths each year.[2] Although significant screening progress has been made, approximately 75% of patients with nonsmall cell lung cancer (NSCLC) are diagnosed at an advanced stage (Stage III or IV), and the survival continues to be poor.[3] For patients with advanced NSCLC who have received multidisciplinary treatments, disease progression usually leads to only palliative and hospice care being available. However, with advances in the fields of tumor biology and immunology, cellular immunotherapies have rapidly become established for treating lung cancer.[1],[4] In 2017, Taiwan's Food and Drug Administration updated the regulations on cellular immunotherapies, allowing hospitals to apply these approaches to patients with serious conditions, for which there was no suitable medication, device, or other therapeutic method available after submitting the treatment protocols.[5] The regulations were formally established in September 2018.

This case report describes the successful treatment of metastatic liver tumors originating from adenocarcinoma of the lung after a 24-week course of autologous immune killer cells (IKC) therapy. The study was approved by Tri-Service General Hospital, National Defense Medical Center. Approval number: B202005066 & Approval Date: 2020/05/13.


  Case Report Top


A 69-year-old nonsmoking woman with a history of hypertension presented at our clinic because of pain over the upper left back and right lateral chest wall for 2 months in 2013. Chest computed tomography showed a mass in the upper right lung with right-sided pleural effusion; moderately differentiated adenocarcinoma of the lung was confirmed after computed tomography-guided biopsy. A whole-body bone scan suggested bone metastasis involving the left scapula; the patient was diagnosed with Stage IV and T4N2M1b disease. The tumor cells harbored sensitive mutation of epidermal growth factor receptor exon 21; thus, tyrosine kinase inhibitor (TKI) therapy with gefitinib was initiated. Owing to disease progression, treatments following the failure of gefitinib included systemic chemotherapy (cisplatin plus pemetrexed, April 2015 to December 2015) and second- and third-line TKIs (erlotinib, December 2015 to March 2016; osimertinib, March 2016 to May 2018). The patient presented general weakness, poor appetite, and body weight loss; newly developed liver metastases were identified in May 2018 [Figure 1]; the circulating level of carcinoembryonic antigen (CEA) arose to 18.87 ng/mL. Thus, local radiotherapy on the metastatic tumors in the liver was applied (May 2018 to July 2018).
Figure 1: Abdominal computed tomography revealed poorly enhanced hepatic masses in the osimertinib treatment period, suggesting liver metastases (arrows)

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Since previous studies elucidated the role of cellular immunotherapies in lung cancer treatment and the established regulations permitting cellular therapies in Taiwan, we initiated autologous cytokine-induced killer (CIK) cell therapy with the cell product of IKCs (Ivy Life Sciences Co. Ltd., Taiwan) after explaining this to the patient. Peripheral blood mononuclear cells were obtained from the patient every week and then were cultured, proliferated, and amplified. Phenotypically, the harvested IKCs included cytotoxic T-cells (Tc; CD3+CD8+CD56−), natural killer T-cells (NKT cells; CD3+CD56+), natural killer cells (NK cells; CD3CD56+), and gamma/delta T-cells (γδ Tc), all free of bacterial and fungal contamination as well as negative for mycoplasma and containing <5 EU endotoxin. The median proportions of the cell population were 80% Tc, 11% NKT cells, 6.1% NK cells, and 2.5% γδ Tc. The median viability of cells was 93.8%.

The patient received IKC intravenously as a monotherapy on a weekly basis from November 2018 to April 2019. A median of 1.98 × 109 cells (range: 1.28–2.38 × 109) was transfused into the patient 24 times during the treatment cycles. Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors 1.1. The metastatic liver tumors were not visible for 3 months after the completion of IKC therapy [Figure 2], while the primary lung tumor and bone metastasis remained stable. The CEA level also decreased (1.55 ng/mL) during the therapeutic period. No adverse effects were recorded; the Eastern Cooperative Oncology Group performance status was Grade 2 after completion of the treatment. The follow-up magnetic resonance imaging of the brain confirmed progressive disease by revealing newly developed brain metastases in September 2019. The progression-free survival (PFS) of IKC therapy in our case was 10 months.
Figure 2: No identifiable liver tumors were found in 3 months after completing the immune killer cells therapy (arrows)

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  Discussion Top


Dysfunctions of cellular immunity, including innate and adaptive immune response, may be one of the reasons for difficulties treating lung cancer.[6] In recent years, cellular immunotherapies were confirmed to play an important role in the maintenance treatment of advanced-stage lung cancer; one meta-analysis suggesting using CIK cells with chemotherapy, particularly autologous CIK cells, can considerably increase the tumor responses, PFS, and overall (1- and 2-year) rates in patients with advanced-stage disease.[7] The therapies alone or in combination with other methodologies also have proven efficient and safe for both NSCLC and small cell lung cancer.[4],[6],[8],[9],[10]

To date, different lymphocyte subsets have been investigated for their effects on lung cancers, including CIK cells, Tc, and γδ Tc. Among them, good cytolytic activity against multiple tumors with CIK cells is well established and is considered to be the most commonly used immunotherapy.[11] CIK cells are a group of heterogeneous cells with distinct populations expressing the cell markers of CD3+CD56 and CD3+CD56+,[4] which function partially as T-lymphocyte and NK cells, explaining their antitumor abilities. Tumor markers of lung cancer in serum were also significantly declined after CIK cell infusion.[12] NK cells are vital to both innate and adaptive immunity by producing cytokines. When activated, NK cells produce cytokines including interferon gamma, tumor necrosis factor alpha, and granulocyte–macrophage colony stimulating factor, exerting cell cytotoxic activities and causing cell lysis.[12] Furthermore, NK cells inhibit the proliferation of lung cancer cells by releasing granzyme B and perforin as cytolytic enzymes,[7] establishing their role in lung cancer treatment. Meanwhile, the Tc can eliminate circulating and disseminating tumor cells originating from a primary tumor,[10] which are untraceable and responsible for distant metastasis. γδ Tc display a synergistic anticancer effect, as previously reported.[8]

Previous studies concluded that cancer stem cells are responsible for tumor progression, metastasis, and the development of drug resistance. Immunocyte-mediated toxicity also affects stem cells; hence, minimal residual disease might be suppressed by cellular immunotherapies, leading to a reduction of cancer recurrence.[8] Cancer employs several mechanisms to escape from immune responses, so cell immunotherapies with only a single type of immune cell may not accomplish a satisfactory antitumor effect. To our patient, we applied autologous IKC with the combination of Tc, NKT cells, NK cells, and γδ Tc as salvage therapy. Each immune cell has anticancer abilities differing from those of others, and they may exert synergistic therapeutic effects for treating metastatic lesions of lung cancer. The enhancing mechanisms remain unclear and require further research. However, local radiotherapy can enhance major histocompatibility complex molecular I expression and stimulate tumor-related antigen release.[13] Our patient had received local radiotherapy at the metastatic hepatic lesions 4 months before IKC therapy, and the effect time of tumor radiation is after 6 months;[13] thus, the interaction of these treatments might act as synergistic in enhancing the body's antitumor immune response.

In conclusion, we reported that autologous IKC therapy might be an effective management approach for refractory or metastatic NSCLC as salvage therapy. It may serve as an option for those patients for whom conventional treatments of lung cancer with disease progression failed, did not generate a response, or were intolerable, for whom only palliative or hospice care is presently available.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature 2018;553:446-54.  Back to cited text no. 1
    
2.
Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ Jr., Wu YL, et al. Lung cancer: Current therapies and new targeted treatments. Lancet. 2017;389:299-311.  Back to cited text no. 2
    
3.
Blandin Knight S, Crosbie PA, Balata H, Chudziak J, Hussell T, Dive C. Progress and prospects of early detection in lung cancer. Open Biol 2017;7:170070.  Back to cited text no. 3
    
4.
Chen D, Sha H, Hu T, Dong S, Zhang J, Liu S, et al. Cytokine-induced killer cells as a feasible adoptive immunotherapy for the treatment of lung cancer. Cell Death Dis 2018;9:366.  Back to cited text no. 4
    
5.
Chen YC, Cheng HF, Yeh MK. Cell therapy regulation in Taiwan. Cell Transplant 2017;26:483-92.  Back to cited text no. 5
    
6.
Zhang J, Zhu L, Du H, He X, Yin Y, Gu Y, et al. Autologous cytokine-induced killer cell therapy in lung cancer patients: A retrospective study. Biomed Pharmacother 2015;70:248-52.  Back to cited text no. 6
    
7.
Xiao Z, Wang CQ, Feng JH, Zhou MH, Wang YZ, Li NN, et al. Effectiveness and safety of chemotherapy with cytokine-induced killer cells in non-small cell lung cancer: A systematic review and meta-analysis of 32 randomized controlled trials. Cytotherapy 2019;21:125-47.  Back to cited text no. 7
    
8.
Ding X, Cao H, Chen X, Jin H, Liu Z, Wang G, et al. Cellular immunotherapy as maintenance therapy prolongs the survival of the patients with small cell lung cancer. J Transl Med 2015;13:158.  Back to cited text no. 8
    
9.
Huang J, Kan Q, Lan, Zhao X, Zhang Z, Yang S, 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;46:170-7.  Back to cited text no. 9
    
10.
Kimura H, Matsui Y, Ishikawa A, Nakajima T, Iizasa T. Randomized controlled Phase III trial of adjuvant chemoimmunotherapy with activated cytotoxic T cells and dendritic cells from regional lymph nodes of patients with lung cancer. Cancer Immunol Immunother 2018;67:1231-8.  Back to cited text no. 10
    
11.
Pan Y, Wu Y, Ji J, Cai H, Wang H, Jiang Y, et al. Effect of cytokine-induced killer cells on immune function in patients with lung cancer. Oncol Lett 2016;11:2827-34.  Back to cited text no. 11
    
12.
Aktaş ON, Öztürk AB, Erman B, Erus S, Tanju S, Dilege Ş. Role of natural killer cells in lung cancer. J Cancer Res Clin Oncol 2018;144:997-1003.  Back to cited text no. 12
    
13.
Reynders K, Illidge T, Siva S, Chang JY, de Ruysscher D. The abscopal effect of local radiotherapy: Using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 2015;41:503-10.  Back to cited text no. 13
    


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