• Journal of Gynecologic Oncology
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• 제29권6호
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• pp.93.1-93.11
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• 2018

The introduction of checkpoint inhibitors revolutionized immuno-oncology. The efficacy of traditional immunotherapeutics, like vaccines and immunostimulants was very limited due to persistent immune-escape strategies of cancer cells. Checkpoint inhibitors target these escape mechanisms and re-direct the immune system to anti-tumor toxicity. Phenomenal results have been reported in entities like melanoma, where no other therapy was able to demonstrate survival benefit, before the introduction of immunotherapeutics. The first experience in ovarian cancer (OC) was reported for nivolumab, a fully human anti-programmed cell death protein 1 (PD1) antibody, in 2015. While the data are extraordinary for a mono-immunotherapeutic agent and very promising, they do not match up to the revolutionary results in entities like melanoma. The key to exceptional treatment response in OC, could be the identification of the most immunogenic patients. We hypothyse that BRCA mutation could be a predictor of improved response in OC. The underlying DNA-repair-deficiancy should result in increased immunogenicity because of higher mutational load and more neoantigen presentation. This hypothesis was not tested to date and should be subject to future trials. The present article gives an overview of the immunologic background of checkpoint inhibition (CI). It presents current data on nivolumab and other checkpoint-inhibitors in solid tumors and OC specifically and depicts important topics in the management of this novel substance group, such as side effect control, diagnostic PD-1/programmed cell death-ligand 1 (PD-L1) expression assessment and management of pseudoprogression.

• Journal of Digestive Cancer Research
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• 제10권1호
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• pp.22-30
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• 2022

Immune checkpoint inhibition has been established as a new treatment option for various types of carcinoma, and many clinical trials are being actively conducted as a treatment for advanced or metastatic gastric cancer, either as a monotherapy with an immune checkpoint inhibitor or as a combination therapy with standard chemotherapy. In the CheckMate-649 clinical trial to confirm the efficacy of the combination of nivolumab and chemotherapy (FP) in advanced gastric cancer and gastroesophageal junction cancer, nivolumab group showed improvement in overall survival in programmed death ligand 1-positive cancer patients compared with placebo group. Also, the combination therapy of pembrolizumab, trastuzumab and chemotherapy (FP) in first-line treatment was tested through the KEYNOTE-811 trial. The pembrolizumab group showed 22.7% of improvement in objective response rate compared with placebo group. Accordingly, the combination of nivolumab/pembrolizumab with standard chemotherapy was approved for the first-line treatment. In KEYNOTE-059 trials for patients with progressive disease after at least two lines of chemotherapy, pembrolizumab monotherapy showed improvement in objective response rate and overall survival, and the use of pembrolizumab was approved for the third-line or more treatment. In this article, we review the result of clinical trials related to immune checkpoint inhibitors that have been recently introduced in the treatment of gastric cancer.

• IMMUNE NETWORK
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• 제20권1호
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• pp.9.1-9.21
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• 2020

Immune checkpoint inhibitors (ICIs) have been changing the paradigm of cancer treatment. However, immune-related adverse effects (irAEs) have also increased with the exponential increase in the use of ICIs. ICIs can break up the immunologic homeostasis and reduce T-cell tolerance. Therefore, inhibition of immune checkpoint can lead to the activation of autoreactive T-cells, resulting in various irAEs similar to autoimmune diseases. Gastrointestinal toxicity, endocrine toxicity, and dermatologic toxicity are common side effects. Neurotoxicity, cardiotoxicity, and pulmonary toxicity are relatively rare but can be fatal. ICI-related gastrointestinal toxicity, dermatologic toxicity, and hypophysitis are more common with anti- CTLA-4 agents. ICI-related pulmonary toxicity, thyroid dysfunction, and myasthenia gravis are more common with PD-1/PD-L1 inhibitors. Treatment with systemic steroids is the principal strategy against irAEs. The use of immune-modulatory agents should be considered in case of no response to the steroid therapy. Treatment under the supervision of multidisciplinary specialists is also essential, because the symptoms and treatments of irAEs could involve many organs. Thus, this review focuses on the mechanism, clinical presentation, incidence, and treatment of various irAEs.

• 대한두경부종양학회지
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• 제33권1호
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• pp.7-13
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• 2017

Despite improved treatment outcomes of locally advanced disease over the last 2 decades, the survival of patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains dismal. There is a clear need for development of novel therapeutic strategies for recurrent and/or metastatic HNSCC. Recent advances in understanding tumor immunology have been directly and rapidly translated into clinical success of T cell-directed immunotherapeutic approach in the treatment of several types of solid cancers. Among them, impact of immune checkpoint inhibition using neutralizing antibodies is the most striking. A variety of immunotherapeutic strategies targeting T cells have been also studied in HNSCC, especially in recurrent and/or metastatic setting even with significant survival benefit. The present article reviews the basic concept of T cell-directed immunotherapy and the current status of such approaches in the treatment of HNSCC.

• IMMUNE NETWORK
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• 제20권1호
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• pp.3.1-3.20
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• 2020

Immune checkpoint inhibitors (ICIs), including anti-PD-1 and anti-CTLA-4 therapeutic agents, are now approved by the Food and Drug Administration for treatment of various types of cancer. However, the therapeutic efficacy of ICIs varies among patients and cancer types. Moreover, most patients do not develop durable antitumor responses after ICI therapy due to an ephemeral reversal of T-cell dysfunction. As co-stimulatory receptors play key roles in regulating the effector functions of T cells, activating co-stimulatory pathways may improve checkpoint inhibition efficacy, and lead to durable antitumor responses. Here, we review recent advances in our understating of co-stimulatory receptors in cancers, providing the necessary groundwork for the rational design of cancer immunotherapy.

• Molecules and Cells
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• 제37권2호
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• pp.126-132
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• 2014

As a tumor suppressor homologue during mitosis, Chk2 is involved in replication checkpoints, DNA repair, and cell cycle arrest, although its functions during mouse oocyte meiosis and early embryo development remain uncertain. We investigated the functions of Chk2 during mouse oocyte maturation and early embryo development. Chk2 exhibited a dynamic localization pattern; Chk2 expression was restricted to germinal vesicles at the germinal vesicle (GV) stage, was associated with centromeres at pro-metaphase I (Pro-MI), and localized to spindle poles at metaphase I (MI). Disrupting Chk2 activity resulted in cell cycle progression defects. First, inhibitor-treated oocytes were arrested at the GV stage and failed to undergo germinal vesicle breakdown (GVBD); this could be rescued after Chk2 inhibition release. Second, Chk2 inhibition after oocyte GVBD caused MI arrest. Third, the first cleavage of early embryo development was disrupted by Chk2 inhibition. Additionally, in inhibitor-treated oocytes, checkpoint protein Bub3 expression was consistently localized at centromeres at the MI stage, which indicated that the spindle assembly checkpoint (SAC) was activated. Moreover, disrupting Chk2 activity in oocytes caused severe chromosome misalignments and spindle disruption. In inhibitor-treated oocytes, centrosome protein ${\gamma}$-tubulin and Polo-like kinase 1 (Plk1) were dissociated from spindle poles. These results indicated that Chk2 regulated cell cycle progression and spindle assembly during mouse oocyte maturation and early embryo development.

• 미생물학회지
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• 제38권2호
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• pp.96-102
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• 2002

S기 checkpoint기작은 DNA복제 저해나 DNA상해 등에 반응하여, S기 세포주기 정지를 일으키거나 상해 회복에 관련된 유전자들의 전사가 유도됨으로서 진핵세포에서의 유전적인 안정성을 유지한다. 이러한 반응에 대한것ba11 변이주의 결손을 확인하기 위해서, nPB11 (DNA polymerase B possible subunit)유전자의 과다발현 효과에 대해 조사하고, HU (Hydroxyurea)와 MMS (Methyl methanesulfonate)에 대한 감수성 및 DNA상해 물질에 의한 RNR3 (Ribonulectide reductase) mRNA의 전사 유도를 조사하였다. RNR3 mRNA의 전사는 DNA합성 저해에 의해 발생한 스트레스나 화학물질에 의한 직접적 인 DNA상해 등에 의해 유도되어진다. 그 결과, dpb11-1변이주는 DNA상해 물질에 감수성을 나타내었고, RNR3 mRNA전사유도 또한 야생형 균주에 비해 약 40% 정도 감소를 나타내었다. 더욱이 dpb2-1 균주에서도 이와 동일한 결과를 얻었다. 그러므로 DPB2와 DPB11 유전자는 복제에 대한 sensor로서, 복제 정지 요인에 대한 세포주기 반응과 전사 조절에 모두 작용하는 것으로 사료된다.

• 약학회지
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• 제46권1호
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• pp.18-23
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• 2002

Ailanthus altissima has been used to settle an upset stomach, to alleviate a fever and as an insecticide. We reported that the water extract of A. altissima induced apoptotic cell death in Jurkat T-acute Iymphoblastic leukemia cells. Here, we showed the dose-dependent inhibitions of cell viability by the extract, as measured by cell morphology. The cell cycle control genes are considered to play important roles in tumorigenesis. The purpose of the present study is also to investigate the effect of A. altissima on cell cycle progression and its molecular mechanism in the cells. The level of p21 protein was increased after treatment of the extract, whereas both Bcl-2 and Bax protein levels were not changed. These results suggest that A. altissima induces apoptotic cell death via p21-dependent signaling pathway in Jurkat cells which delete wild type p53. Gl checkpoint related gene products tested (cyclin D3, cyclin dependent kinase 4, retinoblastoma, E2Fl) were decreased in their protein levels in a dose-dependent manner after treatment of the extract Taken together, these results indicate that the increase of apoptotic cell death by A. altissima may be due to the inhibition of cell cycle in Jurkat cells.

• 생약학회지
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• 제33권1호통권128호
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• pp.29-34
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• 2002

Albizzia julibrissin belonging to the family Leguminosae has been used for the treatment of contusion, sore throat, amnesia, and insomnia in Oriental traditional medicine. The water extract of A. julibrissin induced apoptosis in Jurkat T-acute lymphoblastic leukemia (ALL) cells as measured by cell morphology. The capability of this herb medicine to induce apoptosis was associated with proteolytic cleavage of specific target protein such as beta-catenin protein suggesting the possible involvement of caspases. The purpose of the present study is also to investigate the effect of A. julibrissin on cell cycle progression. Our results showed that GI checkpoint related gene products (cyclin D1, cyclin dependent kinase 4, retinoblastoma, E2F1) were decreased in their protein levels in a dose-dependent manners after treatment of the extract. These results indicate that the increase of apoptotic cell death by A. julibrissin may be due to the inhibition of cell cycle progression in wild type p53-lacking Jurkat cells.

• 대한두경부종양학회지
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• 제33권1호
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• pp.1-5
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• 2017

두경부 편평상피세포암은 전세계적으로 6번째로 흔하며 예후가 불량한 암종이다. 면역 감시는 두경부암의 발생과 진행을 억제하는 중요한 기전으로 알려져 있다. 두경부암세포는 면역 감시를 T세포의 관용을 유도하거나 체크포인트를 통한 T세포 기능을 억제하는 등의 방법으로 회피할 수 있다. 한편 진행성 두경부암 임상연구에서 체크포인트 억제제는 명확한 항종양효과를 입증하였다. 이처럼 면역항암제가 중요한 암치료 방법으로 떠오르는 이때에 본 종설은 두경부암의 면회회피 기전 및 임상적용근거에 대한 최근 지식을 정리하였다.