• IMMUNE NETWORK
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• 제22권5호
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• pp.42.1-42.20
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• 2022

Vaccination with tumor peptide epitopes associated with MHC class I molecules is an attractive approach directed at inducing tumor-specific CTLs. However, challenges remain in improving the therapeutic efficacy of peptide epitope vaccines, including the low immunogenicity of peptide epitopes and insufficient stimulation of innate immune components in vivo. To overcome this, we aimed to develop and test an innovative strategy that elicits potent CTL responses against tumor epitopes. The essential feature of this strategy is vaccination using tumor epitope-loaded nanoparticles (NPs) in combination with polyinosinic-polycytidylic acid (poly-IC) and anti-PD1 mAb. Carboxylated NPs were prepared using poly(lactic-co-glycolic acid) and poly(ethylene/maleic anhydride), covalently conjugated with anti-H-2K^b mAbs, and then attached to H-2K^b molecules isolated from the tumor mass (H-2^b). Native peptides associated with the H-2K^b molecules of H-2K^b-attached NPs were exchanged with tumor peptide epitopes. Tumor peptide epitope-loaded NPs efficiently induced tumor-specific CTLs when used to immunize tumor-bearing mice as well as normal mice. This activity of the NPs significantly was increased when co-administered with poly-IC. Accordingly, the NPs exerted significant anti-tumor effects in mice implanted with EG7-OVA thymoma or B16-F10 melanoma, and the anti-tumor activity of the NPs was significantly increased when applied in combination with poly-IC. The most potent anti-tumor activity was observed when the NPs were co-administered with both poly-IC and anti-PD1 mAb. Immunization with tumor epitope-loaded NPs in combination with poly-IC and anti-PD1 mAb in tumor-bearing mice can be a powerful means to induce tumor-specific CTLs with therapeutic anti-tumor activity.

• Journal of Gastric Cancer
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• 제23권1호
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• pp.224-249
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• 2023

Gastric cancer is heterogeneous in morphology, biology, genomics, and treatment response. Alterations in human epidermal growth factor receptor 2 (HER2) overexpression, microsatellite instability (MSI) status, programmed death-ligand 1 (PD-L1) levels, and fibroblast growth factor receptor 2 (FGFR2) can be used as biomarkers. Since the combination of fluoropyrimidine/platinum plus trastuzumab that was investigated in the ToGA trial was approved as a standard of care in HER2-positive patients in 2010, no other agents showed efficacy in the first- (HELOISE, LOGiC, JACOB trials) and second- (TyTAN, GATSBY, T-ACT trials) line treatments. Despite the success in treating breast cancer, various anti-HER2 agents, including a monoclonal antibody (pertuzumab), an antibody-drug conjugate (ADC; trastuzumab emtansine [T-DM1]), and a small molecule (lapatinib) failed to translate into clinical benefits until the KEYNOTE-811 (first-line) and DESTINY-Gastri01 (≥second-line) trials were conducted. The incorporation of HER2-directed treatment with immune checkpoint inhibitors in the form of a monoclonal antibody or ADC is now approved as a standard treatment. Despite the promising results of new agents (engineered monoclonal antibodies, bi-specific antibodies, fusion proteins, and small molecules) in the early phase of development, the management of HER2-positive gastric cancer requires further optimization to achieve precision medicine with a chemotherapeutic backbone. Treatment resistance is a complex process that can be overcome using a combination of chemotherapy, targeted agents, and immune checkpoint inhibitors, including novel agents. HER2 status must be reassessed in patients undergoing anti-HER2 treatment with disease progression after the first-line treatment. As a general guideline, patients who need systemic treatment should receive chemotherapy plus targeted agents, anti-angiogenic agents, immune checkpoint inhibitors, or their combinations.

• International journal of thyroidology
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• 제11권2호
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• pp.172-175
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• 2018

Anti-programmed cell death-1 (PD-1) humanized monoclonal antibody inhibits PD-1 activity by binding to the PD-1 receptor on T-cells and blocking PD-1 ligands and induces immune tolerance of cancer cells. It has been widely used for various kinds of cancer treatment. However, many immune-related adverse events (irAEs) have been reported because it modulates our immune system. In this case study, we reported a case of 42-year-old woman with Hashimoto's thyroiditis who showed rapid aggravation of thyroid goiter and acute hyperventilation syndrome after treatment with PD-1 inhibitor as a neoadjuvant chemotherapy for breast cancer.

• Journal of Veterinary Science
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• 제25권1호
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• pp.15.1-15.15
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• 2024

Background: The anti-programmed death 1 (PD-1) antibody has led to durable clinical responses in a wide variety of human tumors. We have previously developed the caninized anti-canine PD-1 antibody (ca-4F12-E6) and evaluated its therapeutic properties in dogs with advance-staged oral malignant melanoma (OMM), however, their therapeutic effects on other types of canine tumors remain unclear. Objective: The present clinical study was carried out to evaluate the safety profile and clinical efficacy of ca-4F12-E6 in dogs with advanced solid tumors except for OMM. Methods: Thirty-eight dogs with non-OMM solid tumors were enrolled prospectively and treated with ca-4F12-E6 at 3 mg/kg every 2 weeks of each 10-week treatment cycle. Adverse events (AEs) and treatment efficacy were graded based on the criteria established by the Veterinary Cooperative Oncology Group. Results: One dog was withdrawn, and thirty-seven dogs were evaluated for the safety and efficacy of ca-4F12-E6. Treatment-related AEs of any grade occurred in 13 out of 37 cases (35.1%). Two dogs with sterile nodular panniculitis and one with myasthenia gravis and hypothyroidism were suspected of immune-related AEs. In 30 out of 37 dogs that had target tumor lesions, the overall response and clinical benefit rates were 6.9% and 27.6%, respectively. The median progression-free survival and overall survival time were 70 days and 215 days, respectively. Conclusions: The present study demonstrated that ca-4F12-E6 was well-tolerated in non-OMM dogs, with a small number of cases showing objective responses. This provides evidence supporting large-scale clinical trials of anti-PD-1 antibody therapy in dogs.

• Journal of Gastric Cancer
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• 제23권1호
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• pp.207-223
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• 2023

Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Under the standard of care, patients with advanced GC (AGC) have a median survival time of approximately 12-15 months. With the emergence of immunotherapy as a key therapeutic strategy in medical oncology, relevant changes are expected in the systemic treatment of GC. In the phase III ATTRACTION-2 trial, nivolumab, a monoclonal anti-programmed cell death 1 (PD-1) antibody, as a third- or later-line treatment improved overall survival (OS) compared with placebo in patients with AGC. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment improved OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the global phase III CheckMate-649 study. Another anti-PD-1 antibody, pembrolizumab, in combination with trastuzumab and cytotoxic chemotherapy as a first-line treatment, significantly improved the overall response rate in patients with HER2-positive AGC. Therefore, immune checkpoint inhibitors (ICIs) are essential components of the current treatment of GC. Subsequent treatments after ICI combination therapy, such as ICI rechallenge or combination therapy with agents having other modes of action, are being actively investigated to date. On the basis of the success of immunotherapy in the treatment of AGC, various clinical trials are underway to apply this therapeutic strategy in the perioperative and postoperative settings for patients with early GC. This review describes recent progress in immunotherapy and potential immunotherapy biomarkers for GC.

• 대한핵의학회지
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• 제30권4호
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• pp.541-547
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• 1996

우리는 국내에서 개발한 항 NCA-95 단일클론항체의 면역학적 특성을 규명하고 $^{99m}Tc$ 표지법을 연구하여 골수면역 신티그라피법을 개발한 바 있다. 그러나 $^{99m}Tc$ 단일클론항체의 표지효율이 낮고, 과정이 복잡하여 시간이 오래 걸리는 단점이 있어 임상적용에 어려움이 있었다. 본 연구에서는 $^{99m}Tc$ 표지 단일클론항체의 표지과정을 개선하여 시간을 단축하고 표지효율을 높이는 연구를 실시하였다. 티올기와 아민 및 하이드록시 그룹을 가진 착화제(chelator)와 $^{99m}Tc$은 안정한 복합체를 형성하므로, 이러한 화학적 성질을 이용하여 항체를 환원시켜 티올기를 생성하고 여기에 약한 착화제와 결합한 $^{99m}Tc$을 가하는 transchelation법을 연구하였다. 본 연구에서는 방법 1. ${\beta}$-mercaptoethanol로 항체를 환원하고 환원제의 존재하에 $^{99m}Tc$-gluconate 를 이용한 표지법, 방법 2. 항체의 환원후 ${\beta}$-mercaptoethanol을 제거하고 $^{99m}Tc$-gluconate를 사용한 표지법, 방법 3. 환원제를 제거한 항체에 MDP를 먼저 가하고 여기에 $^{99m}Tc$을 가하는 표지법을 시도하여 보았다. 고정상으로는 ITLC-SG를, 이동상으로는 생리식염수와 아세톤을 사용하여 표지효율을 구하였다. 방법 1은 표지효율이 40-70%이나 좋은 골수영상을 얻었고, 방법 2의 경우 표지효율은 70-80%로 개선되었으나 혈액풀의 방사능이 높았다. MDP를 착화제로 이용한 방법 3은 표지효율이 $92.4{\pm}5.9%$(n=15) 이고 면역반응성은 약 60%였으며 골수면역 신티그라피에서도 좋은 영상을 얻을 수 있었다. 때로는 $^{99m}Tc$- MDP 방사능이 높아 뼈에 흡수되는 방사능이 증가하는 단점이 있지만 PD-10 컬럼을 이용하여 분리가 가능하였다. 환원된 항체를 냉동보관하여 사용하였을 경우에도 안정하여 냉동보관 47일 까지 90%이상의 표지효율을 보였다. 본 연구 결과 $^{99m}Tc$ 표지 항 NCA-95 단일클론항체의 표지법의 개선으로 더 쉽게 임상에 이용할 수 있게 될 것으로 생각된다.