• IMMUNE NETWORK
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• v.5 no.3
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• pp.157-162
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• 2005

Background: 1-8D gene is a member of human 1-8 interferon inducible gene family and was shown to be overexpressed in fresh colon cancer tissues. Three peptides 1-6, 3-5 and 3-7 derived from human 1-8D gene were shown to have immunogenicity against colon cancer. Methods: To study tumor immunotherapy, of three peptides we established an active immunization model using HHD mice. $D^{b-/-}{\times}{\beta}2$ microglobulin $({\beta}2m)$ null mice transgenic for a chimeric HLA-$A2.1/D^{b-}\;{\beta}2m$ single chain (HHD mice) were challenged with B16/HHD/1-8D tumor cells and were immunized with irradiated peptide-loaded RMA- S/HHD/B7.1 transfectants. In therapy model tumor growth was retarded in HHD mice that were injected with 3-5 peptide-loaded RMA-S/HHD/B7.1. In survival test vaccination with 1-8D-derived peptide protects HHD mice from tumor progression after tumor challenge. Results: These studies show that peptide 3-5 derived from 1-8D gene can be the most effective candidate for the vaccine of immunotherapy against colon cancer and highlight 1-8D gene as putative colon carcinoma associated antigens. Conclusion: We demonstrated that RMA-S/HHD/ B7.1 loaded with 1-8D peptides, especially 3-5, immunization generates potent antitumor immunity against tumor cells in HHD mice and designed active immunization as proper immunotherapeutic protocols.

• Molecules and Cells
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• v.42 no.12
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• pp.869-883
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• 2019

Interleukin (IL)-15 is an essential immune-modulator with high potential for use in cancer treatment. Natural IL-15 has a low biological potency because of its short half-life and difficulties in mass-production. IL-15Rα, a member of the IL-15 receptor complex, is famous for its high affinity to IL-15 and its ability to lengthen the half-life of IL-15. We have double-transfected IL-15 and its truncated receptor IL-15Rα into CT26 colon cancer cells to target them for intracellular assembly. The secreted IL-15:IL-15Rα complexes were confirmed in ELISA and Co-IP experiments. IL-15:IL-15Rα secreting clones showed a higher anti-tumor effect than IL-15 secreting clones. Furthermore, we also evaluated the vaccine and therapeutic efficacy of the whole cancer-cell vaccine using mitomycin C (MMC)-treated IL-15:IL-15Rα secreting CT26 clones. Three sets of experiments were evaluated; (1) therapeutics, (2) vaccination, and (3) long-term protection. Wild-type CT26-bearing mice treated with a single dose of MMC-inactivated secreted IL-15:IL-15Rα clones prolonged survival compared to the control group. Survival of MMC-inactivated IL-15:IL-15Rα clone-vaccinated mice (without any further adjuvant) exceeded up to 100%. This protection effect even lasted for at least three months after the immunization. Secreted IL-15:IL-15Rα clones challenging trigger anti-tumor response via CD4⁺ T, CD8⁺ T, and natural killer (NK) cell-dependent cytotoxicity. Our result suggested that cell-based vaccine secreting IL-15:IL-15Rα, may offer the new tools for immunotherapy to treat cancer.

• BMB Reports
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• v.54 no.7
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• pp.386-391
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• 2021

Owing to rapid advancements in NGS (next generation sequencing), genomic alteration is now considered an essential predictive biomarkers that impact the treatment decision in many cases of cancer. Among the various predictive biomarkers, tumor mutation burden (TMB) was identified by NGS and was considered to be useful in predicting a clinical response in cancer cases treated by immunotherapy. In this study, we directly compared the lab-developed-test (LDT) results by target sequencing panel, K-MASTER panel v3.0 and whole-exome sequencing (WES) to evaluate the concordance of TMB. As an initial step, the reference materials (n = 3) with known TMB status were used as an exploratory test. To validate and evaluate TMB, we used one hundred samples that were acquired from surgically resected tissues of non-small cell lung cancer (NSCLC) patients. The TMB of each sample was tested by using both LDT and WES methods, which extracted the DNA from samples at the same time. In addition, we evaluated the impact of capture region, which might lead to different values of TMB; the evaluation of capture region was based on the size of NGS and target sequencing panels. In this pilot study, TMB was evaluated by LDT and WES by using duplicated reference samples; the results of TMB showed high concordance rate (R² = 0.887). This was also reflected in clinical samples (n = 100), which showed R² of 0.71. The difference between the coding sequence ratio (3.49%) and the ratio of mutations (4.8%) indicated that the LDT panel identified a relatively higher number of mutations. It was feasible to calculate TMB with LDT panel, which can be useful in clinical practice. Furthermore, a customized approach must be developed for calculating TMB, which differs according to cancer types and specific clinical settings.

• The Korean Journal of Physiology and Pharmacology
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• v.27 no.3
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• pp.241-256
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• 2023

Although chimeric antigen receptor T cell (CAR-T) is a promising immunotherapy in hematological malignancies, there remain many obstacles to CART cell therapy for solid tumors. Identifying appropriate tumor-associated antigens (TAAs) is especially critical for success. Using a bioinformatics approach, we identified common potential TAAs for CAR-T cell immunotherapy in solid tumors. We used the GEO database as a training dataset to find differentially expressed genes (DEGs) and verified candidates using the TCGA database, obtaining seven common DEGs (HM13, SDC1, MST1R, HMMR, MIF, CD24, and PDIA4). Then, we used MERAV to analyze the expression of six genes in normal tissues to determine the ideal target genes. Finally, we analyzed tumor microenvironment factors. The results of major microenvironment factor analyses showed that MDSCs, CXCL1, CXCL12, CXCL5, CCL2, CCL5, TGF- β, CTLA-4, and IFN-γ were significantly overexpressed in breast cancer. The expression of MST1R was positively correlated with TGF- β, CTLA-4, and IFN-γ. In lung adenocarcinoma, MDSCs, Tregs, CXCL12, CXCL5, CCL2, PD-L1, CTLA-4, and IFN-γ were significantly overexpressed in tumor tissues. The expression of MST1R was positively correlated with TGF- β, CTLA-4, and IFN-γ. In bladder cancer, CXCL12, CCL2, and CXCL5 were significantly overexpressed in tumor tissues. MST1R expression was positively correlated with TGF- β. Our results demonstrate that MST1R has the potential as a new target antigen for treating breast cancer, lung adenocarcinoma, and bladder cancer and may be used as a progression indicator for bladder cancer.

• Biomedical Science Letters
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• v.25 no.3
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• pp.201-210
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• 2019

The oncolytic viruses selectively infect and destroy cancer cells, not harming normal cells. The cancer cell materials released by oncolysis, like tumor antigens, stimulate host antitumor immune responses, which is a long-lasting antitumor immunity removing cancer cells in remote parts of the body by a systemic response. Oncolytic viruses armed with transgenes such as cytokines or other immune stimulating factors enhance the immune responses. The first oncolytic virus approved by US-FDA is $Imlygic^{(R)}$ targeting for melanoma. The oncolytic virus is considered as a revolutionary immunotherapy for tumors together with immune checkpoint inhibitors. A variety of oncolytic viruses are under research in the treatment of kidney cancer, liver cancer, breast cancer, and many others solid tumors. Clinical trials have shown promising results in different types of cancers. Here, we present a brief introduction of various aspects of oncolytic virus, and a review of the current status of oncolytic virus therapy development.

• Korean Journal of Head & Neck Oncology
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• v.38 no.1
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• pp.1-9
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• 2022

Thyroid cancer is one of the slow-growing tumors with excellent oncological outcomes. However, a small set of patients with unexpectedly severe outcomes are usually ignored. Anaplastic thyroid cancer (ATC) remains one of the most aggressive and lethal solid tumors. Recently, dabrafenib and trametinib combination therapy or neoadjuvant BRAF induction therapy has shown promising results. In addition, a combination of targeted drugs, immunotherapy, surgery, and radiation therapy can improve overall survival in ATC patients. Another disease for which there is no breakthrough treatment is radioactive iodine-refractory differentiated thyroid cancer (DTC). To date, multikinase inhibitors (sorafenib, lenvatinib) targeting the growth factor signaling pathway have been developed and approved as anticancer agents for patients with advanced DTC. This review includes results from multikinase inhibitors to the emergence of new target molecules, including rearrangements during transformation (RET) and tropomyosin receptor kinase (TRK).

• Journal of the Korean Medical Association
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• v.61 no.11
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• pp.662-669
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• 2018

The cutaneous melanoma has been regarded as rare disease entity in Korea for long time but it shows a silent growth recently. Furthermore the management of cutaneous melanoma including staging system, surgical principle, sentinel lymph node biopsy and subsequent complete node dissection and, most importantly, immunotherapy and target therapy against cutaneous melanoma recently. The incidence of cutaneous melanoma is steadily increasing in Korea but its increase is rapid recent 2 decades to 4.3 times and should be greater soon according to the steeper increase of life expectancy. New staging system proposed by American Joint Committee on Cancer (2017) includes changes in individual TNM category and stage groups, particularly from a prognostic viewpoint. Dermoscopy has been successfully introduced in the differential diagnosis of pigmented skin lesion focusing on cutaneous melanoma by non-invasive simple diagnostic tool. Sentinel lymph node biopsy was a issue of long debate whether survival benefit is real or not. Temporary conclusion about this question is reached after two large scale studies and immediate complete node dissection should be performed in a certain situations. Most important change is drug therapy focusing on immunotherapy and target therapy. Braf- and MEK-inhibitor, immune checkpoint inhibitor and PD-1 blocker has been proved to be effective as a sole or combination regimen against advanced and/or high-risk adjuvant setting of cutaneous melanoma. In conclusion, these remarkable changes will be reviewed shortly here.

• Journal of Sensor Science and Technology
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• v.32 no.6
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• pp.418-424
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• 2023

Natural killer (NK) cells play a crucial role in combating infections and tumors. However, their therapeutic application in solid tumors is hindered by challenges, such as limited lifespan, tumor penetration, and delivery precision. Our research introduces a novel ultrasonic actuation technique to navigate NK cells more effectively in the vascular system, particularly at vessel bifurcations where targeted delivery is most problematic. We use a hemispherical ultrasonic transducer array that generates phase-modulated traveling waves, focusing on an ultrasound beam to steer NK cells using blood-flow dynamics and a focused acoustic field. This method enables the precise obstruction of non-target vessels and efficiently directs NK cells toward the tumor site. The simulation results offer insights into the behavior of NK cells under various conditions of cell size, radiation pressure, and fluid velocity, which inform the optimization of their trajectories and increase targeting efficiency. The experimental results demonstrate the feasibility of this ultrasonic approach for enhancing NK cell targeting, suggesting a potential leap forward in solid tumor immunotherapy. This study represents a significant step in NK cell therapeutic strategies, offering a viable solution to the existing limitations and promising enhancement of the efficacy of cancer treatments.

• IMMUNE NETWORK
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• v.21 no.3
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• pp.23.1-23.16
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• 2021

Chemokines are key factors that influence the migration and maintenance of relevant immune cells into an infected tissue or a tumor microenvironment. Therefore, it is believed that the controlled administration of chemokines in the tumor microenvironment may be an effective immunotherapy against cancer. Previous studies have shown that CCL3, also known as macrophage inflammatory protein 1-alpha, facilitates the recruitment of dendritic cells (DCs) for the presentation of tumor Ags and promotes T cell activation. Here, we investigated the role of CCL3 in regulating the tumor microenvironment using a syngeneic mouse tumor model. We observed that MC38 tumors overexpressing CCL3 (CCL3-OE) showed rapid regression compared with the wild type MC38 tumors. Additionally, these CCL3-OE tumors showed an increase in the proliferative and functional tumor-infiltrating T cells. Furthermore, PD-1 immune checkpoint blockade accelerated tumor regression in the CCL3-OE tumor microenvironment. Next, we generated a modified CCL3 protein for pre-clinical use by fusing recombinant CCL3 (rCCL3) with a non-cytolytic hybrid Fc (HyFc). Administering a controlled dose of rCCL3-HyFc via subcutaneous injections near tumors was effective in tumor regression and improved survival along with activated myeloid cells and augmented T cell responses. Furthermore, combination therapy of rCCL3-HyFc with PD-1 blockade exhibited prominent effect to tumor regression. Collectively, our findings demonstrate that appropriate concentrations of CCL3 in the tumor microenvironment would be an effective adjuvant to promote anti-tumor immune responses, and suggest that administering a long-lasting form of CCL3 in combination with PD-1 blockers can have clinical applications in cancer immunotherapy.

• IMMUNE NETWORK
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• v.23 no.5
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• pp.41.1-41.21
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• 2023

CD4 and CD8 T cells are key players in the immune response against both pathogenic infections and cancer. CD4 T cells provide help to CD8 T cells via multiple mechanisms, including licensing dendritic cells (DCs), co-stimulation, and cytokine production. During acute infection and vaccination, CD4 T cell help is important for the development of CD8 T cell memory. However, during chronic viral infection and cancer, CD4 helper T cells are critical for the sustained effector CD8 T cell response, through a variety of mechanisms. In this review, we focus on T cell responses in conditions of chronic Ag stimulation, such as chronic viral infection and cancer. In particular, we address the significant role of CD4 T cell help in promoting effector CD8 T cell responses, emerging techniques that can be utilized to further our understanding of how these interactions may take place in the context of tertiary lymphoid structures, and how this key information can be harnessed for therapeutic utility against cancer.