Cancer Research and Treatment

Original Articles

Lung and Thoracic cancer

A Phase I/IIa Randomized Trial Evaluating the Safety and Efficacy of SNK01 Plus Pembrolizumab in Patients with Stage IV Non-Small Cell Lung Cancer: Eo Jin Kim, Yong-Hee Cho, Dong Ha Kim, Dae-Hyun Ko, Eun-Ju Do, Sang-Yeob Kim, Yong Man Kim, Jae Seob Jung, Yoonmi Kang, Wonjun Ji, Myeong Geun Choi, Jae Cheol Lee, Jin Kyung Rho, Chang-Min Choi; Cancer Res Treat. 2022;54(4):1005-1016. Published online December 3, 2021; DOI: https://doi.org/10.4143/crt.2021.986

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Purpose
The aim of this study is to evaluate the safety and efficacy of ex vivo activated and expanded natural killer (NK) cell therapy (SNK01) plus pembrolizumab in a randomized phase I/IIa clinical trial.
Materials and Methods
Overall, 18 patients with advanced non–small cell lung cancer (NSCLC) and a programmed death ligand 1 tumor proportion score of 1% or greater who had a history of failed frontline platinum-based therapy were randomized (2:1) to receive pembrolizumab every 3 weeks +/– 6 weekly infusions of SNK01 at either 2×10⁹ or 4×10⁹ cells per infusion (pembrolizumab monotherapy vs. SNK01 combination). The primary endpoint was safety, whereas the secondary endpoints were the objective response rate (ORR), progression-free survival (PFS), overall survival, and quality of life.
Results
Since no dose-limiting toxicity was observed, the maximum tolerated dose was determined as SNK01 4×10⁹ cells/dose. The safety data did not show any new safety signals when SNK01 was combined with pembrolizumab. The ORR and the 1-year survival rate in the NK combination group were higher than those in patients who underwent pembrolizumab monotherapy (ORR, 41.7% vs. 0%; 1-year survival rate, 66.7% vs. 50.0%). Furthermore, the median PFS was higher in the SNK01 combination group (6.2 months vs. 1.6 months, p=0.001).
Conclusion
Based on the findings of this study, the NK cell combination therapy may consider as a safe treatment method for stage IV NSCLC patients who had a history of failed platinum-based therapy without an increase in adverse events.

Citations

Citations to this article as recorded by

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NK cell infusion is well-tolerated and shows preliminary efficacy in patients with recurrent hepatocellular carcinoma post-liver transplantation : a phase I trial
Fan Yang, Yihang Gong, Xiaofang Zheng, Beibei Ni, Jianxi Lu, Xiaoyan Chen, Jintao Cheng, Panlong Li, Cong Du, Yunhao Chen, Yingcai Zhang, Shuhong Yi, Guoying Wang, Qi Zhang, Yang Yang, Wenjie Chen
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Lucie Biard, Vincent Lévy, Sylvie Chevret, Annette Künkele, Stefanie Grunwald, Alessandro Aiuti, Bjarne Kuno Møller, Reno Debets, Stephan Mielke, Johan van Eldere, Antonia Müller, Silvia Martin Lluesma, Lorena Consolino, Matt Bolz-Johnson, Stefano Benvenu
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Lymphoma

Forkhead Box C1 (FOXC1) Expression in Stromal Cells within the Microenvironment of T and NK Cell Lymphomas: Association with Tumor Dormancy and Activation: Ji Hae Nahm, Woo Ick Yang, Sun Och Yoon; Cancer Res Treat. 2020;52(4):1273-1282. Published online July 3, 2020; DOI: https://doi.org/10.4143/crt.2020.032

Abstract PDF Supplementary Material PubReader ePub

Purpose
Forkhead box C1 (FOXC1) is critical for maintaining bone marrow microenvironments during hematopoiesis, but its role in hematological malignancies remains obscure. Here, we investigated whether FOXC1 regulates tumor dormancy and activation in the microenvironments of T and natural killer (NK) cell lymphomas.
Materials and Methods
One hundred and twenty cases of T and NK cell lymphomas were included; the immunohistochemical expression of FOXC1 was investigated in stromal cells, and numbers of FOXC1⁺ stromal cells were counted. Furthermore, the expression of phosphorylated p38 (p-p38) and phosphorylated ERK1/2 (p-ERK1/2) in tumor cells was investigated using immunohistochemistry.
Results
FOXC1 was variably expressed in C-X-C motif chemokine 12–associated reticular stromal cells, histiocytes, (myo)fibroblasts, and endothelial cells. The phenotypes of cases were categorized as dormant (high p-p38/low p-ERK1/2; n=30, 25.0%), active (high p-ERK1/2/low p-p38; n=25, 20.8%), or intermediate (others; n=65, 54.2%). Lower FOXC1⁺ stromal cell infiltration was associated with the dormant phenotype, the precursor T lymphoblastic leukemia/lymphoma subtype, and inferior overall survival rates, whereas higher FOXC1⁺ stromal cell infiltration was associated with the active phenotype and favorable patient prognosis (p < 0.05 for all).
Conclusion
These results suggested that FOXC1⁺ stromal cells within the microenvironments of T and NK cell lymphomas might be related to tumor phenotypes.

Citations

Citations to this article as recorded by

Mechanisms of lymphoma-stromal interactions focusing on tumor-associated macrophages, fibroblastic reticular cells, and follicular dendritic cells
Rintaro Ohe
Journal of Clinical and Experimental Hematopathology.2024; 64(3): 166. CrossRef

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Peripheral Blood Natural Killer Cell Activity and Its Clinical Role in Lymphomas: Own Gyu Uh, Yang Soo Kim, Byung Chae Park; J Korean Cancer Assoc. 1995;27(3):504-513.

Abstract PDF: Purpose
We designed this investigation to evaluate the association of NK activity with vari- ous clinical and laboratory data, and to evaluate whether NK activity can be used as a valuable prognostic factor since there is no systemic review on natural killer cell(NK) activity of peripheral blood in untreated lymphomas in Korea. Method: Forty-eight patients admitted to Dept. of Internal Medicine of Kosin University Hospital from JuL l989 to Feb. 1995 were enrolled. The target of effector cells was K562 cell line and released Cr(51) during 4 hours was counted. Then, NK activity was compared with varous c1inical and laboratary data. We selected International Index, composed of 4 risk groups derived from 5 risk factors, as a prognostic factor to evaluate the value of NK activity, and it was compared with the result of NK activity. The International Index was composed of 4 risk groups: low, low-intermediate, high-intermediate, and high risk groups. Results: 1) The sex ratio of the patients was 1.2: #1 and the median age was 55 years. Diffuse large cell lymphoma was the most common subtype(52.1%). 2) The average NK activity of lymphoma patients was 43.85% and that of normal control was 51.54%, and the difference was significant(F=0.003). 3) The NK activity of the patients was significantly different depending on clinical stage, B symptom or performance status(P=0.003, O.Q33, and 0.016 respectively), but not on age, sex or serum LDH leveL 4) In 4 risk groups, there was progressive decrease in NK activity as the risk increases(P=O. 001), and the differences in NK activity between low and high-intermediate groups and low and high risk groups were all significant(P=0.002 both). 5) NK activity of normal control was significantly different from 3 of 4 risk groups, low-in- termediate, high-intermediate and high risk groups, of patients(P=0.021, 0.001, 0.001 respectively). Concluaion: In previously untreated lymphoma patients, the NK activity was decreased, and NK activity was inversely carrelated with risk status(P=0.001). In conclusion, NK activity may have a prognostic value, and clinical trials with many patients and long-term follow uP as to assess survival are required.

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Natural Killer ( NK ) Cell cytotoxicity According to the Expression of c-erbB-2 Protein in Human Gastric Cancer Cells: Byeong Woo Park, Kang Sup Shim, Sung Hoon Noh, Coong Bai Kim, Kyung Shik Lee; J Korean Cancer Assoc. 1995;27(1):1-8.

Abstract PDF: Although there is still controversy to the relationship between c-erbB-2 protein expression and prognosis of the gastric carcinoma, there were many reports about the poor prognosis with the expression of c-erbB-2 in gastric carcinoma. The mechanisms underlying this phenomenon are not known. However several possibilities such as acquired resistance to 5-Fluorouracil(5-FU) and resistance to the host immune system were suggested. So we performed this study to evaluate whether c-erbB-2 expression can alter the natural killeriNK) cell cytotoxic activity. Using single cell suspensions from primary gastric cancer tissues and malignant ascites due to stomach cancer, the immunohistochemical reactivity to c-cerB-2 protein was examined and we performed the tests for NK cell cytotoxic activity. The c-erbB-2(+) cancer cells were significantly more resistant to NK cell cytotoxic activity than c-erbB-2( ) cancer cells. However there was no significant difference in the resiatance to NK cell cytotoxic activity according to their immunohistochemical staining intensities. These results suggest that the resistance to the NK cel1 cytotoxicity may be one of the possi- ble mechanisms of the poorer prognosis of the c-erbB-2(+ ) gastric cancers.

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