• IMMUNE NETWORK
• /
• 제20권1호
• /
• pp.11.1-11.14
• /
• 2020

Most patients with hepatocellular carcinoma (HCC) are diagnosed at an advanced stage of disease. Until recently, systemic treatment options that showed survival benefits in HCC have been limited to tyrosine kinase inhibitors, antibodies targeting oncogenic signaling pathways or VEGF receptors. The HCC tumor microenvironment is characterized by a dysfunction of the immune system through multiple mechanisms, including accumulation of various immunosuppressive factors, recruitment of regulatory T cells and myeloid-derived suppressor cells, and induction of T cell exhaustion accompanied with the interaction between immune checkpoint ligands and receptors. Immune checkpoint inhibitors (ICIs) have been interfered this interaction and have altered therapeutic landscape of multiple cancer types including HCC. In this review, we discuss the use of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies in the treatment of advanced HCC. However, ICIs as a single agent do not benefit a significant portion of patients. Therefore, various clinical trials are exploring possible synergistic effects of combinations of different ICIs (anti-PD-1/PD-L1 and anti-CTLA-4 antibodies) or ICIs and target agents. Combinations of ICIs with locoregional therapies may also improve therapeutic responses.

• Asian Pacific Journal of Cancer Prevention
• /
• 제13권6호
• /
• pp.2795-2798
• /
• 2012

Objective: This study is conducted to evaluate the effects of anti-HER-2${\times}$anti-CD3 bi-specific antibodies(BsAb) on HER-2/neuover-expressing human colorectal carcinoma cells. Methods: Growth was assessed by MTT assays after exposure of HCT-116 cells to Herceptin, anti-CD3 and BsAb antibodies. Immunocytochemistry was applied to test the HER-2 level of HCT-116. In a nude mouse model, HER-2${\times}$CD3 BsAb was combined with effector cells (peripheral blood lymph cells from normal human being) for observations on in Vivo growth of tumors. Results: Compared with the control group, using effector cells combined with anti-CD3 McAb, Herceptin or HER2${\times}$CD3 BsAb, tumor cell growth in vitro and in vivo was significantly inhibited (P<0.05), most remarkably in the HER2${\times}$CD3 BsAb case. The growth of xenografts with HER2${\times}$CD3 BsAb combined with effector cells was also significantly inhibited when compared with the anti-CD3 McAb or Herceptin groups (P<0.05). Conclusion: HER-2/neu might be a useful target for immunotherapy in colorectal carcinoma, anti-HER2${\times}$anti-CD3 BsAb exerting clear anti-tumor effects.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권10호
• /
• pp.4367-4372
• /
• 2014

We here document discovery of expression profile of myeloid derived suppressor cells (MDSCs) in chronic hepatitis B (CHB) patients and changes in the course of disease. The study population was composed of 75 outpatient HBV cases and 15 healthy control cases. Peripheral blood samples were collected for separation of mononuclear cells. Levels of MDSCs labeled with Lin-DR-CD11b+CD33+ obtained from peripheral blood mononuclear cells (PBMC), were revealed to have significant differences between the CHB and other groups. They were 0.414% for health control cases and 0.226% for CHB cases (Z=-2.356, p=0.0189). It also observed that the group of HBeAg positive cases had significant difference in MDSCs/PBMC median ($X^2=11.877$, p=0.003), compared with group of HBeAg negative cases and the healthy control group. It suggested considerable MDSCs might be involved in HBeAg immune tolerance. In addition, negative correlations between MDSCs/PBMC and parameters of ALT, AST and TBil, while positive correlation between MDSCs/PBMC and ALB parameter were found. Multiple comparisons between the four phases and health control phase again, there was a statistically sifnificant difference ($X^2=17.198$, p=0.002). Taken together, these findings may provide a new immunotherapy strategy for reduced the expression levels of MDSCs in CHB patients, through induction of an autoimmune response to virus removal.

• Journal of Gastric Cancer
• /
• 제6권3호
• /
• pp.193-197
• /
• 2006

흑색종은 피부나 점막에 존재하는 멜라닌 세포에서 기원하는 악성 종양으로 피부에 가장 흔하게 발생한다. 위장관계 점막에서도 흑색종이 발생할 수 있는데 원발성은 매우 드물고 대부분은 피부의 원발성 흑색종으로부터 전이되어 나타난다. 위에 발생한 원발성 흑색종은 매우 드물고 치료 성적이 나쁘고 전이 속도가 빨라서 예후가 매우 나쁘다. 저자들은 혈변, 복통과 체중 감소를 주소로 내원한 75세 남자로 수술 전 진행성 위암으로 진단되어 위전절제술을 시행하였으나 수술 후 위 분문부의 원발성 흑색종으로 식도-위 접합부까지 침범한 증례를 경험하였기에 문헌 고찰과 함께 보고하는 바이다. 흑색종 치료에서 수술은 가장 표준적인 치료법이다. 수술 후 보조 요법으로 항암화학요법, 방사선 치료, 면역 치료 등을 시도해 보았지만 생존율 증가가 입증된 치료 방법은 아직 없는 실정이다. 장기간 생존율을 향상시키기 위해서는 조기 진단과 수술적 치료가 가장 중요하다.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권18호
• /
• pp.7857-7861
• /
• 2014

Natural killer (NK) cells play an important role in anti-tumor immunity. Interleukin (IL)-18 is an immunoregulatory cytokine that induces potent NK cell-dependent anti-tumor responses when administrated with other cytokines. In this study, we explored the effects of combining IL-18 and IL-2 on NK cytotoxicity as well as expression levels of the NK cell receptor NKG2D in vitro. Freshly isolated PBMCs were incubated for 48 h with IL-18 and IL-2, then CD107a expression on $CD3^-CD56^+$ NK cells was determined by three-colour flow cytometry to evaluate the cytotoxicity of NK cells against human erythroleukemia K562 cells and human colon carcinoma HT29 cells. Flow cytometric analysis was also employed to determine NKG2D expression on NK cells. The combined use of IL-18 and IL-2 significantly increased CD107a expression on NK cells compared with using IL-18 or IL-2 alone, suggesting that the combination of these two cytokines exerted synergistic enhancement of NK cytotoxicity. IL-18 also enhanced NKG2D expression on NK cells when administered with IL-2. In addition, blockade of NKG2D signaling with NKG2D-blocking antibody attenuated the up-regulatory effect of combining IL-18 and IL-2 on NK cytolysis. Our data revealed that IL-18 synergized with IL-2 to dramatically enhance the cytolytic activity of human NK cells in a NKG2D-dependent manner. The results appear encouraging for the use of combined IL-18 and IL-2 in tumor immunotherapy.

• Asian Pacific Journal of Cancer Prevention
• /
• 제16권10호
• /
• pp.4329-4333
• /
• 2015

Background: To investigate the change of frequency and immuno-inhibitory function of myeloid-derived suppressor cells (MDSCs) after treatment of cisplatin (DDP) in A375 human melanoma model. Materials and Methods: BALB/c nude mice were inoculated with A375 cells to establish the human melanoma model and randomly divided into control group given normal saline (NS) and experimental group treated with DDP (5 mg/kg). The percentages of MDSCs in the tumor tissue and peripheral blood after DDP treatment were detected by flow cytometry. The proliferation and interferon-${\gamma}$ (IFN-${\gamma}$) secretion of T cells co-cultured with MDSCs were analyzed through carboxyfluorescein succinimidyl ester (CFSE) labeling assay and enzyme-linked immunospot (ELISPOT) assay, respectively. Results: In A375 human melanoma model, DDP treatment could significantly decrease the percentage of MDSCs in the tumor tissue, but exerted no effect on the level of MDSCs in peripheral blood. Moreover, DDP treatment could attenuate the immuno-inhibitory function of MDSCs. T cells co-cultured with DDP-treated MDSCs could dramatically elevate the proliferation and production of INF-${\gamma}$. Conclusions: DDP can decrease the frequency and attenuate immuno-inhibitory function of MDSCs in A375 melanoma model, suggesting a potential strategy to augment the efficacy of combined immunotherapy.

• 한국임상약학회지
• /
• 제21권4호
• /
• pp.319-331
• /
• 2011

Purpose: The purpose of this study is to evaluate current criteria for insurance coverage by Health Insurance Review & Assessment Service (HIRA) on the systemic therapy used in the treatment of advanced or metastatic renal cell carcinoma (RCC), by reviewing all available clinical evidences including a variety of clinical practice guidelines. Methods: We searched clinical databases and collected data from published phase 1 through 3 randomized clinical trials on all systemic therapies used in RCC, including novel targeted therapies. Additionally, current clinical practice guidelines on the management of kidney cancer or RCC were reviewed. Based on the collected data we evaluated the appropriateness of the HIRA criteria for insurance coverage on the systemic therapy of RCC whether they are evidence-based and up to date. Results: On the basis of the collected data we concluded that there was a need for a revision in HIRA criteria for systemic therapy of RCC. Despite recent emerging therapeutic advances and changes in therapeutic strategies of management of RCC, some of anticancer regimens were inappropriately listed even though they were not proven to provide efficacy or safety superior to those of other therapies. We thus proposed an updated recommendation based on current clinical evidences. Conclusion: Systemic therapy of RCC is being rapidly changed with the advancement of understanding of the molecular biology of cancer. Consequently newly developed targeted therapies are becoming the standard therapy in the management of medically or surgically unresectable advanced or metastatic RCC. To provide effective and safe therapy to patients with RCC, the criteria for insurance coverage should be made carefully taking into consideration of most up-to-date and high-quality clinical evidences, and should be continuously reviewed so as to reflect evidence-based clinical practice.

• Korean Journal of Radiology
• /
• 제22권4호
• /
• pp.584-595
• /
• 2021

Objective: Immune checkpoint inhibitor (ICI) therapy has shown activity against melanoma brain metastases. Recently, promising results have also been reported for ICI combination therapy and ICI combined with radiotherapy. We aimed to evaluate radiologic response and adverse event rates of these therapeutic options by a systematic review and meta-analysis. Materials and Methods: A systematic literature search of Ovid-MEDLINE and EMBASE was performed up to October 12, 2019 and included studies evaluating the intracranial objective response rates (ORRs) and/or disease control rates (DCRs) of ICI with or without radiotherapy for treating melanoma brain metastases. We also evaluated safety-associated outcomes. Results: Eleven studies with 14 cohorts (3 with ICI combination therapy; 5 with ICI combined with radiotherapy; 6 with ICI monotherapy) were included. ICI combination therapy {pooled ORR, 53% (95% confidence interval [CI], 44-61%); DCR, 57% (95% CI, 49-66%)} and ICI combined with radiotherapy (pooled ORR, 42% [95% CI, 31-54%]; DCR, 85% [95% CI, 63-95%]) showed higher local efficacy compared to ICI monotherapy (pooled ORR, 15% [95% CI, 11-20%]; DCR, 26% [95% CI, 21-32%]). The grade 3 or 4 adverse event rate was significantly higher with ICI combination therapy (60%; 95% CI, 52-67%) compared to ICI monotherapy (11%; 95% CI, 8-17%) and ICI combined with radiotherapy (4%; 95% CI, 1-19%). Grade 3 or 4 central nervous system (CNS)-related adverse event rates were not different (9% in ICI combination therapy; 8% in ICI combined with radiotherapy; 5% in ICI monotherapy). Conclusion: ICI combination therapy or ICI combined with radiotherapy showed better local efficacy than ICI monotherapy for treating melanoma brain metastasis. The grade 3 or 4 adverse event rate was highest with ICI combination therapy, and the CNS-related grade 3 or 4 event rate was similar. Prospective trials will be necessary to compare the efficacy of ICI combination therapy and ICI combined with radiotherapy.

• Korean Journal of Radiology
• /
• 제22권3호
• /
• pp.366-375
• /
• 2021

Objective: To evaluate the radiological tumor response patterns and compare the response assessments based on immune-based therapeutics Response Evaluation Criteria in Solid Tumors (iRECIST) and RECIST 1.1 in metastatic clear-cell renal cell carcinoma (mccRCC) patients treated with programmed cell death-1 (PD-1) inhibitors. Materials and Methods: All mccRCC patients treated with PD-1 inhibitors at Henan Cancer Hospital, China, between January 2018 and April 2019, were retrospectively studied. A total of 30 mccRCC patients (20 males and 10 females; mean age, 55.6 years; age range, 37-79 years) were analyzed. The target lesions were quantified on consecutive CT scans during therapy using iRECIST and RECIST 1.1. The tumor growth rate was calculated before and after therapy initiation. The response patterns were analyzed, and the differences in tumor response assessments of the two criteria were compared. The intra- and inter-observer variabilities of iRECIST and RECIST 1.1 were also analyzed. Results: The objective response rate throughout therapy was 50% (95% confidence interval [CI]: 32.1-67.9) based on iRECIST and 30% (95% CI: 13.6-46.4) based on RECIST 1.1. The time-to-progression (TTP) based on iRECIST was longer than that based on RECIST 1.1 (median TTP: not reached vs. 170 days, p = 0.04). iRECIST and RECIST 1.1 were discordant in 8 cases, which were evaluated as immune-unconfirmed PD based on iRECIST and PD based on RECIST 1.1. Six patients (20%, 6/30) had pseudoprogression based on iRECIST, of which four demonstrated early pseudoprogression and two had delayed pseudoprogression. Significant differences in the tumor response assessments based on the two criteria were observed (p < 0.001). No patients demonstrated hyperprogression during the study period. Conclusion: Our study confirmed that the iRECIST criteria are more capable of capturing immune-related atypical responses during immunotherapy, whereas conventional RECIST 1.1 may underestimate the benefit of PD-1 inhibitors. Pseudoprogression is not rare in mccRCC patients during PD-1 inhibitor therapy, and it may last for more than the recommended maximum of 8 weeks, indicating a limitation of the current strategy for immune response monitoring.

• Tuberculosis and Respiratory Diseases
• /
• 제53권3호
• /
• pp.265-274
• /
• 2002

배 경 :종양 특이 항원인 MAGE 유전자는 여러 종류의 암조직에서 발현되지만 정상조직에서는 고환의 생식 세포를 제외하고는 발현이 없다. 본 연구에서는 MAGE 유전자의 암 특이적 발현을 폐암의 진단에 활용할 수 있는지를 유도객담을 이용하여 알아보고자 하였다. 방 법 :조직학적으로 폐암으로 진단된 환자 30명, 대조군으로 기타 폐질환 환자 14명에서 얻은 유도객담을 3cc의 보존제(guanidinium isothiocyanate, Triton X-100)와 잘 섞어 냉장보관 후 당일 MAGE A 1-6를 동시에 발견할 수 있도록 고안된 2종류의 primer(MAGE common primer C1/C2, C3/C4)를 이용하여 nested PT PCR를 실시하여 MAGE 유전자의 발현 유무를 조사하였다. 결 과 : MAGE common primer를 이용한 nested RT-PCR에서 폐암환자 30 명 중 24명 (80%)에서 MAGE가 양성으로 발현되었고 대조군에서는 전례에서 발견되지 않았다(p=0.001). 편평세포암 17례 중 13례(76.5%), 선암 9례 중 7례 (77.8%)에서 소세포암은 4례에서 모두 MAGE 양성이었으며 각 군간에 발현율의 차이는 없었다(p=0.56). MAGE양성인 환자 24명 중 약 반수인 11 명에서는 기관지 내시경검사에서 육안적으로 종양 병변이 발견되지 않는 경우였다. 결 론 : 유도객담에서 MAGE 유전자는 암 환자에서 선택적으로 높은 빈도의 발현을 보이는 것을 확인하였다. 이러한 결과로 객담을 이용한 MAGE 검사법이 폐암의 검색, 조기진단 그리고 치료 후 경과 관찰에 유용하게 사용될 수 있을 것으로 생각된다.