Adoptive CTL therapy using neo-antigen-specific TCR-gene induced T cells

使用新抗原特异性 TCR 基因诱导 T 细胞进行过继 CTL 治疗

• 批准号: 21K08751
• 负责人: 村田 聡
• 金额: $ 2.75万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K08751/
• 关键词: 癌免疫細胞療法; ネオ抗原; CTL; PDX; 免疫チェックポイント阻害薬; OX40; TCR改変リンパ球; 免疫細胞治療; PDXマウス

新規抗原(Neo-Ag)特異的細胞傷害性T細胞(CTL)を利用する養子免疫療法の有効性が少規模の臨床研究で示されているが、Neo-Ag同定の非効率さやCTLの生体内での不活性化、腫瘍の免疫逃避機構の克服が課題である。我々は既存技術より優れたNeo-Ag同定法と担癌生体内でメモリー機能の維持が可能なCTL培養技術を独自に開発した。　本研究は、患者由来Neo-Ag反応性T細胞受容体遺伝子で自己Tリンパ球を改変し、in vitroでOX40刺激により効率よくメモリー機能を付与させ、さらに腫瘍免疫逃避機構解除の抗PD-1薬を組み合わせた後にpatient-derived xenograft (PDX)マウスへ移入することにより抗腫瘍効果を証明する。1）PDXモデルの作成；患者のNeo-Ag特異的メモリーCTLが同一患者の腫瘍に対して生体で抗腫瘍機能を発揮することを確かめるため、大腸癌手術患者1名、胃癌手術患者1名、乳癌手術患者1名から患者腫瘍を摘出（Ｆ０腫瘍）し、NOGマウス（免疫不全マウス）の皮下に移植し、生着した腫瘍（F1)を摘出し、さらにNOGマウスに移植して生着した腫瘍（F2)を摘出し凍結保存できた。患者リンパ球由来ＴＣＲ改変ＣＴＬが誘導できた後に患者腫瘍を用いた抗腫瘍効果実験が可能となる。2）Neo-Ag候補の同定； 大腸癌、胃癌、乳癌患者の癌組織および正常組織より抽出したDNAのwhole exome sequenceにて、癌組織での体細胞突然変異を同定している。アミノ酸変異を伴う変異に絞り、RNA transcriptome解析でRNA発現を示す変異遺伝子を同定しNetMHCを用い患者HLA-class Iに親和性の高い変異抗原ペプチドをNeo-Ag候補として同定しているところである。

The cellular nociceptive T cell (CTL) specific to the new rule antigen (Neo-Ag) was used to study the immune response rate of CTL in vivo and the immune evasion mechanism of immune evasion mechanism to overcome the problem. We study the existing technology and Neo-Ag method to maintain the ability of cancer patients to maintain the ability of CTL training technology on their own. In this study, the cause of the Neo-Ag reactivating T cell receptor receptor was that the T cell receptor was modified, the in vitro OX40 was stimulated, the immune escape mechanism was paid, and the immune escape mechanism was used to remove the anti-PD-1 antibody. The anti-patient-derived xenograft (PDX) antibody was transferred into the immune system and the results showed that the anti-HBV antibody was not effective. 1) the PDX has been completed. The Neo-Ag-specific anti-tumor machine of the same patient was able to make sure that the tumor was successfully removed, 1 patient with large cancer, 1 patient with gastric cancer, 1 patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, one patient with breast cancer, one patient with gastric cancer, "NOG", "Transplant", "born", "F2", "extract", "Save". The cause of the disease is that the TCR changed the CTL guidance, and the patients were treated with antiretroviral therapy, and the results showed that the patients might be affected. 2) the Neo-Ag phenotype was the same as that in the patients with large cancer, gastric cancer and breast cancer, the normal tissue was extracted from the normal tissue, the DNA whole exome sequence was extracted from the normal tissue, and the somatic cells of the cancer tissue were suddenly identified. RNA transcriptome analysis showed that the RNA showed that the patients had the same HLA-class I as the patients' HLA-class and the patients with high sex had the same antigen as those with the Neo-Ag phenotype.

项目成果

Relationship between CD44-positive cancer stem-like cells and gastric cancer-derived peritoneal metastasis

CD44阳性肿瘤干细胞样细胞与胃癌腹膜转移的关系

• 发表时间: 2021
• 作者: Andreas Michael Sihombing1;Satoshi Murata1,2;Miyuki Shimoji1;Sakura Nakao1;Katsushi Takebayashi1;Hirokazu Kodama1;Masatsugu Kojima1;Tomoyuki Ueki1;Naomi Kitamura3;Mina Kitamura1;Aya Tokuda1;Toru Miyake1;Eiji Mekata3;Masaji Tani1
• 通讯作者: Masaji Tani1

Crosstalk of microsomal glutathione transferase 1 (MGST1) and CD44 in T3M4 human pancreatic cancer cells on hyperthermic model

高温模型下 T3M4 人胰腺癌细胞中微粒体谷胱甘肽转移酶 1 (MGST1) 和 CD44 的串扰

• 发表时间: 2021
• 作者: Miyuki Shimoji1;Satoshi Murata1,2;Andreas Michael Sihombing1;Sakura Nakao1;Katsushi Takebayashi1;Hirokazu Kodama1;Masatsugu Kojima1;Tomoyuki Ueki1;Naomi Kitamura3;Mina Kitamura1;Aya Tokuda1;Toru Miyake1;Eiji Mekata3;Masaji Tani1
• 通讯作者: Masaji Tani1

Characterization of Tumor-associated lymphocytes (TAL) in malignant ascites of immune-tolerant mice

免疫耐受小鼠恶性腹水中肿瘤相关淋巴细胞 (TAL) 的表征

• 发表时间: 2021
• 作者: Miyuki Shimoji 1);Satoshi Murata 2);Masatsugu Kojima 1);Mina Kitamura 1);Andreas Michael Sihombing 1);Sakura Nakao 1);Naomi Kitamura 3);Tomoyuki Ueki 1);Katsushi Takebayashi 1);Hirokazu Kodama 1);Aya Tokuda 1);Toru Miyake 1);Eiji Mekata 3);Ma
• 通讯作者: Ma

Overcoming immune tolerance to tumor antigens and inducing tumor antigen-specific CTLs by combined immunotherapy

通过联合免疫疗法克服对肿瘤抗原的免疫耐受并诱导肿瘤抗原特异性CTL

• 发表时间: 2021
• 作者: Sakura Nakao;Satoshi Murata;Miyuki Shimoji;Masatsugu Kojima;Mina Kitamura;Andreas Michael Sihombing;Naomi Kitamura;Tomoyuki Ueki;Katsushi Takebayashi;Hirokazu Kodama;Aya Tokuda;Toru Miyake;Eiji Mekata;Masaji Tani
• 通讯作者: Masaji Tani

CD44+ cancer cells in the free peritoneal cavity and surgical manipulation as the cause of gastric cancer-derived peritoneal metastasis

游离腹膜腔中的CD44癌细胞和手术操作导致胃癌腹膜转移的原因

• 发表时间: 2021
• 作者: Andreas Michael Sihombing1;Satoshi Murata1,2;Miyuki Shimoji1;Sakura Nakao1;Katsushi Takebayashi1;Hirokazu Kodama1;Masatsugu Kojima1;Tomoyuki Ueki1;Naomi Kitamura3;Mina Kitamura1;Aya Tokuda1;Toru Miyake1;Eiji Mekata3;Masaji Tani1
• 通讯作者: Masaji Tani1