Details of a Researcher

Research Projects of Competitive Funds, etc. - Ueda, Ryo

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難治性脳腫瘍血管を標的としたペプチドワクチン療法の新規治療効果予測因子の検証

2024.04

2027.03

基盤研究(C), Principal investigator

悪性脳腫瘍に対するウイルス搭載iPS細胞を用いた新規治療の開発

2021.04

2024.03

Keio University, Grant-in-Aid for Scientific Research (B), No Setting

難治性脳腫瘍新生血管を標的としたペプチドワクチン療法の臨床効果予測因子の検証

2021.04

2024.03

Keio University, Grant-in-Aid for Scientific Research (C), No Setting

本研究では、難治性脳腫瘍に対するペプチドワクチン療法臨床試験被験者の様々な検体を用いて個々の患者における正・負の免疫動態を総合的に評価し、①同ペプチドワクチン療法の効果が期待できる症例の選出方法開発（免疫療法の有効性を予測するための免疫バイオマーカー探索）、②免疫バイオマーカーにより同免疫療法と抗がん剤との組み合わせなどの免疫制御法の改良技術を評価する。本研究成果は、本治療に対する治療反応性予測を可能にし、治療成績向上につながる可能性がある。また、脳腫瘍免疫および脳腫瘍血管新生・浸潤性における新たな機構の解明につながり、治療困難な脳腫瘍の治療成績の改善に貢献することが期待される。

悪性脳腫瘍新生血管を治療標的としたペプチドワクチン療法の有効性予測因子の解明

2018.04

2021.03

MEXT,JSPS, Grant-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (C), Principal investigator

Biomarkers for evaluation of clinical activity of VEGFR-targeted vaccines against malignant glioma patients

2015.04

2018.03

Keio University, UEDA RYO, TODA MASAHIRO, Grant-in-Aid for Scientific Research (C), No Setting

Evaluation of immunological biomarkers may lead to better understanding of the critical immune response indicators that may help to predict clinical responses of cancer immunotherapy. We characterized status of immune cells, cytokines, chemokines, and other immunosuppressive molecules in malignant glioma patients who received vaccinations of VEGF receptor (VEGFR)-derived peptides. Peripheral blood samples from patients who demonstrated positive radiologic response or stable disease revealed superior VEGFR-specific CTL reactivity and lower level of serum VEGF compared to samples from other patients with progressing malignant glioma. Plasma IL-8 level was negatively correlated with overall survival. These data indicate that these parameters may be potential immune-biomarkers for evaluation of clinical activity of VEGFR-targeted vaccines.

Immunotherapy targeting brain tumor stem cell antigen and niche

2012.04

2015.03

Keio University, TODA Masahiro, UEDA Ryo, Grant-in-Aid for Challenging Exploratory Research, No Setting

In this study, we demonstrated that glioma cells and brain tumor stem cells (BTSCs) expressed highly VEGF (vascular endothelial growth factor) and VEGFR (vascular endothelial growth factor receptor) in vitro. Furthermore, VEGFR was shown to express highly within malignant glioma tissues compared with surrounding brain tissue. In a clinical study, we performed a novel immunotherapy using VEGFR1/VEGFR2 peptides in 8 patients with recurrent malignant glioma and analyzed the cytotoxic T lymphocytes (CTLs) specific to VEGFR1/VEGFR2.　After the vaccination with VEGFR1/VEGFR2, CTLs specific to VEGFR1 were induced in 6 out of 6 patients analyzed and CTLs specific to VEGFR2 in 2 out of 6 patients. These results suggest that an immunotherapy using VEGFR1/2 peptides to inhibit the VEGF/VEGFR signal may be effective for the treatment of malignant glioma.

Immune-biomarkers for evaluation of clinical activity of VEGFR-targeted vaccines against malignant glioma patients

2012.04

2015.03

Keio University, UEDA RYO, TODA Masahiro, Grant-in-Aid for Scientific Research (C), No Setting

Immune-biomarkers and -assays are important for development of cancer immunotherapy to monitor immune induction following immunotherapy, and to evaluate anti-tumor effects early after immunotherapy. We characterized status of immune cells, cytokines, chemokines and other immunosuppressive molecules in recurrent malignant glioma patients who received vaccinations of VEGF receptor peptides. Peripheral blood samples from patients who demonstrated positive radiologic response or stable disease revealed superior VEGFR-specific CTL reactivity and lower level of serum VEGF compared to samples from other patients with progressing malignant glioma. These data indicate that these parameters may be potential immune-biomarkers for evaluation of clinical activity of VEGFR-targeted vaccines.

Analysis of stemness regulators in brain cancer stem cells

2010

2012

Keio University, TODA Masahiro, UEDA Ryo, Grant-in-Aid for Scientific Research (B), No Setting

MicroRNA-222 is a potential target for developing blood-based diagnostic methods and treatment of malignant glioma

2010

2011

Keio University, UEDA Ryo, Grant-in-Aid for Young Scientists (B), No Setting

We previously reported that microRNA(miR)-222 over-expressed in cancer cells down-regulates ICAM-1, thereby reducing cancer cell susceptibility to cytotoxic T lymphocytes(CTLs). In this study, we found that miR-222 was up-regulated in some of human glioma tissues. Inhibition of miR-222 led to recovery of ICAM-1 expression in glioma cell lines, resulting in restoration of their susceptibility to CTL-mediated cytolysis. Thus, the increased miR-222 expression may contribute to glioma escape from the host immune surveillance. We then found that miR-222 could be detected by quantitative PCR in serum of glioma patients. Moreover, the elevated miR-222 expression was associated with disease progression and poor prognosis of the patients, suggesting possible development of new diagnostic methods for malignant characteristics of glioma and prognosis of the patients. Interestingly, miR-222 containing exosomes secreted from glioma cells may be uptaken by dendritic cells(DCs), and decreased ICAM-1 expression on DC, which is important for T cell activation. These results indicate that miR-222 may be a potential target for developing novel diagnostic and therapeutic methods for glioma patients.

Development of immunotherapy based on the identification of tumor antigens

2005

2009

Keio University, KAWAKAMI Yutaka, FUJITA Tomonobu, SAKURAI Toshiharu, KUDO Chie, TSUKAMOTO Nobuo, UEDA Ryo, MATSUZAKI Yuriko, TSUKAMOTO Makoto, Grant-in-Aid for Scientific Research on Priority Areas, No Setting

Cancer immunotherapy has not been established as a standard cancer therapy. To improve current immunotherapy, in this project we have identified new human tumor antigens, revealed cancer immune responses particularly cancer induced immunosuppression, and evaluated immunological characteristics of cancer stem cells and epithelial-mesenchymal transitioned cancer cells. Newly identified tumor antigens and immune modulation methods may lead to development of new diagnostic and therapeutic methods for cancer.

CD4及びCD8陽性T細胞に認識されるグリオーマ抗原を用いた特異的免疫療法の確立

2005

2006

Keio University, Grant-in-Aid for Young Scientists (B), No Setting

近年CD8陽性T細胞活性の増強や維持にはCD4陽性T細胞が重要な役割を担っていることが明らかになった。我々は、グリオーマ患者血清を用いたSEREX (serological identification of antigens by recombinant expression cloning)法により、精巣組織由来のcDNA libraryをスクリーニングしたところ、胎生期に転写調節因子として機能するSOX6を単離した。さらにSOX6は、グリオーマ組織において高い発現を示し、グリオーマ患者血清中IgG抗体に高頻度に認識されることから、SOX6が抗原特異的にCD4陽性T細胞を活性化していることが示唆された。そこで、グリオーマ担癌マウスモデルにおいて、CD8陽性T細胞に認識される抗原としてマウスグリオーマ由来新規抗原遺伝子GARC-1を、CD4陽性T細胞が認識する抗原としてSOX6を用いた腫瘍特異的免疫の活性化を試みた。GARC-1とSOX6それぞれの全長を含んだplasmid DNAをC57BL/6マウス皮内に遺伝子銃による免疫を行い、免疫マウスの脾細胞を用いて両抗原を発現しているマウス由来のグリオーマ細胞GL261をターゲットにしたIFN-γ assayを行ったところ、GARC-1とSOX6双方で免疫した群では各々単独で免疫した群やコントロール群と比してGL261に対するIFN-γ放出量の著明な増加を示した。このことから、GARC-1とSOX6双方で免疫した群ではGL261に対する特異的細胞障害性T細胞が誘導されたことが示唆された。また、最終ワクチンから2週間後に、免疫マウスの頭蓋内にGL261細胞を移植し、腫瘍の生着および増殖能を生存期間により検討したところ、GARC-1とSOX6双方で免疫した群ではコントロール群と比して有意に生存期間が延長された。
これらの結果から、CD4陽性T細胞を活性化し得るSEREX抗原SOX6とCD8陽性T細胞に認識されるグリオーマ抗原両者を用いた免疫遺伝子治療によって、グリオーマ細胞に対する特異的細胞障害性が増強され、さらに腫瘍拒絶能を向上し得ることが示された。このことから、グリオーマ抗原SOX6を用いたDNAワクチンは、グリオーマに対する免疫遺伝子治療に応用できる可能性があると考えられる。

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