Development of tailor-made iPS-DC cancer vaccine therapy targeting Neoantigen

• Project/Area Number: 20K09063
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Wakayama Medical University
• Principal Investigator: OJIMA TOSHIYASU 和歌山県立医科大学, 医学部, 講師 (60448785)
• Co-Investigator(Kenkyū-buntansha): 山上 裕機 和歌山県立医科大学, 医学部, 学長特命教員(特別顧問) (20191190) ; 北谷 純也 和歌山県立医科大学, 医学部, 助教 (30596979) ; 中村 公紀 和歌山県立医科大学, 医学部, 非常勤講師 (80364090)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がんワクチン / iPS細胞 / 樹状細胞 / ネオアンチゲン / ペプチド / Neoantigen / 腫瘍抗原

Outline of Research at the Start

マウス実験ではC57BLマウスメラノーマモデルにおいて腫瘍mRNA導入iPS-DCのワクチン効果を検証する．消化器固形がん患者を対象にCTOS法を用いて腫瘍細胞をライン化し，そのCTOSよりmRNAを患者由来iPS-DCに遺伝子導入する．In vitroで得られたCTLがCTOSに対し，抗腫瘍効果を発揮するか否かを検証する．さらにNeoantigenを同定し，おのおのneo特異的なCTLが誘導可能であることをin vitroで立証する．上記作業仮説が立証されたら，免疫チェックポイント阻害剤を組み合わせた複合免疫療法の可能性を立証する予定である．

Outline of Final Research Achievements

In this study, we use amplified mRNA from human colorectal cancer cells, synthesized them by in vitro transcription, and transfected iPSDCs with in vitro transcriptional RNA (ivtRNA). We examine whether the ivtRNA-transfected iPSDCs induce tumor-specific cytotoxic T lymphocytes (CTLs) and whether these antitumor responses are directed against multiple TAAs.
Our studies clearly demonstrate that the high immunogenicity of iPSDCs-ivtRNA was generated by transfecting tumor RNA. By transfecting ivtRNA of CTOSs prepared from surgical specimens into iPSDCs generated from patients with colorectal cancer, we succeeded in inducing CTLs in vitro for the first time. In addition, these CTLs showed an immune response to a neoantigen. Ultimately, our findings revealed that iPSDCs-ivtRNA paves the way for a promising DC vaccine therapy.

Academic Significance and Societal Importance of the Research Achievements

我々の研究の最終目標は各患者由来iPS細胞を駆使した個別のiPS-DCワクチン療法という究極のテーラーメイドがんワクチン療法の構築である．
今回の研究におけるiPS-DCワクチン療法の研究成果は前臨床試験として世界にインパクトを与えるとともに，多くの難治性消化器固形癌患者に大きな希望を与えると確信する．

Research Products

• [Journal Article] Risk Factors of Postoperative Intra-Abdominal Infectious Complications after Robotic Gastrectomy for Gastric Cancer. (2022)
  • Author(s): Ojima T, Hayata K, Kitadani J, Takeuchi A, Yamaue H.
  • Journal Title: Oncology Volume: 100 Issue: 11 Pages: 583-590
  • DOI: 10.1159/000526920
  • Peer Reviewed
• [Journal Article] Risk Factors for Chronic Atrial Fibrillation Development After Esophagectomy for Esophageal Cancer (2022)
  • Author(s): Kashiwagi Manabu、Ojima Toshiyasu、Hayata Keiji、Kitadani Junya、Takeuchi Akihiro、Kuroi Akio、Terada Kosei、Tanimoto Takashi、Tanaka Atsushi、Yamaue Hiroki
  • Journal Title: Journal of Gastrointestinal Surgery Volume: 26 Issue: 12 Pages: 2451-2459
  • DOI: 10.1007/s11605-022-05493-9
  • Peer Reviewed
• [Journal Article] Feeding jejunostomy following esophagectomy may increase the occurrence of postoperative small bowel obstruction. (2022)
  • Author(s): Nakai T, Kitadani J, Ojima T, Hayata K, Katsuda M, Goda T, Takeuchi A, Tominaga S, Fukuda N, Nagano S, Yamaue H.
  • Journal Title: Medicine Volume: 101 Issue: 37 Pages: e30746-e30746
  • DOI: 10.1097/md.0000000000030746
  • Peer Reviewed / Open Access
• [Journal Article] Nutritional benefit of remnant gastric preservation in patients with esophageal cancer undergoing radical esophagectomy and ileo-colon interposition. (2022)
  • Author(s): Kitadani J, Ojima T, Hayata K, Goda T, Takeuchi A, Katsuda M, Tominaga S, Fukuda N, Nakai T, Nagano S, Yamaue H.
  • Journal Title: BMC Surgery Volume: 22 Issue: 1 Pages: 255-255
  • DOI: 10.1186/s12893-022-01704-x
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic distal gastrectomy for synchronous adenocarcinoma, diffuse large B cell lymphoma and gastrointestinal stromal tumor in the stomach: a case report (2022)
  • Author(s): Ojima T, Tabata H, Yamaue H.
  • Journal Title: Surgical Case Reports Volume: 8 Issue: 1 Pages: 89-89
  • DOI: 10.1186/s40792-022-01446-1
  • Peer Reviewed / Open Access
• [Journal Article] Tumor RNA transfected DCs derived from iPS cells elicit cytotoxicity against cancer cells induced from colorectal cancer patients in vitro (2022)
  • Author(s): Maruoka S, Ojima T, Iwamoto H, Kitadani J, Tabata H, Tominaga S, Katsuda M, Hayata K, Takeuchi A, Yamaue H.
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 3295-3295
  • DOI: 10.1038/s41598-022-07305-1
  • Peer Reviewed / Open Access
• [Journal Article] Robotic Ivor Lewis esophagectomy for gastroesophageal junction cancer (with video). (2022)
  • Author(s): Ojima T, Hayata K, Yamaue H.
  • Journal Title: J Visc Surg. Volume: 159 Issue: 2 Pages: 171-172
  • DOI: 10.1016/j.jviscsurg.2021.11.004
  • Peer Reviewed
• [Journal Article] Venous Invasion Is a Risk Factor for Recurrence of pT1 Gastric Cancer with Lymph Node Metastasis. (2022)
  • Author(s): Takeuchi A, Ojima T, Katsuda M, Hayata K, Goda T, Kitadani J, Tominaga S, Fukuda N, Nakai T, Yamaue H.
  • Journal Title: J Gastrointest Surg. Volume: 26 Issue: 4 Pages: 757-763
  • DOI: 10.1007/s11605-021-05238-0
  • Peer Reviewed
• [Journal Article] Robotic curative para-aortic lymph node dissection via INfra-mesocolon for gastric cancer: Robotic CAVING approach. (2021)
  • Author(s): Ojima T, Hayata K, Kitadani J, Yamaue H.
  • Journal Title: Surg Oncol. Volume: 39 Pages: 101658-101658
  • DOI: 10.1016/j.suronc.2021.101658
  • Peer Reviewed
• [Journal Article] Short-term Outcomes of Robotic Gastrectomy vs Laparoscopic Gastrectomy for Patients With Gastric Cancer: A Randomized Clinical Trial. (2021)
  • Author(s): Ojima T, Nakamura M, Hayata K, Kitadani J, Katsuda M, Takeuchi A, Tominaga S, Nakai T, Nakamori M, Ohi M, Kusunoki M, Yamaue H.
  • Journal Title: JAMA Surg. Volume: 156 Issue: 10 Pages: 954-963
  • DOI: 10.1001/jamasurg.2021.3182
  • Peer Reviewed
• [Journal Article] Comparison of short-term surgical outcomes using da Vinci S, Si and Xi Surgical System for robotic gastric cancer surgery. (2021)
  • Author(s): Ojima T, Nakamura M, Hayata K, Kitadani J, Takeuchi A, Yamaue H.
  • Journal Title: Sci Rep. Volume: 11 Issue: 1 Pages: 11063-11063
  • DOI: 10.1038/s41598-021-90741-2
  • Peer Reviewed / Open Access
• [Journal Article] Curative para-Aortic lymph node dissection Via INfra-mesocolonic approach in laparoscopic Gastrectomy (CAVING approach). (2021)
  • Author(s): Hayata K, Ojima T, Nakamura M, Kitadani J, Takeuchi A, Yamaue H.
  • Journal Title: Langenbecks Arch Surg. Volume: 406 Issue: 6 Pages: 2067-2074
  • DOI: 10.1007/s00423-021-02198-6
  • Peer Reviewed
• [Journal Article] Esophagogastrostomy With Fundoplication Versus Double-tract Reconstruction After Laparoscopic Proximal Gastrectomy for Gastric Cancer. (2021)
  • Author(s): Tominaga S, Ojima T, Nakamura M, Katsuda M, Hayata K, Kitadani J, Takeuchi A, Motobayashi H, Nakai T, Yamaue H.
  • Journal Title: Surg Laparosc Endosc Percutan Tech. Volume: 31 Issue: 5 Pages: 594-598
  • DOI: 10.1097/sle.0000000000000948
  • Peer Reviewed
• [Journal Article] Robotic Subtotal Gastrectomy with Small Remnant Stomach for Gastric Cancer in the Upper Stomach. (2021)
  • Author(s): Ojima T, Nakamura M, Hayata K, Kitadani J, Takeuchi A, Yamaue H.
  • Journal Title: J Gastrointest Surg. Volume: 25 Issue: 8 Pages: 2165-2171
  • DOI: 10.1007/s11605-021-05025-x
  • Peer Reviewed
• [Journal Article] Oncolytic virotherapy with SOCS3 enhances viral replicative potency and oncolysis for gastric cancer (2021)
  • Author(s): Matsumura Shuichi、Nakamori Mikihito、Tsuji Toshiaki、Kato Tomoya、Nakamura Masaki、Ojima Toshiyasu、Fukuhara Hiroshi、Ino Yasushi、Todo Tomoki、Yamaue Hiroki
  • Journal Title: Oncotarget Volume: 12 Issue: 4 Pages: 344-354
  • DOI: 10.18632/oncotarget.27873
  • Peer Reviewed / Open Access
• [Journal Article] Safety and feasibility of laparoscopic gastrectomy for remnant gastric cancer compared with open gastrectomy: Single-center experience. (2021)
  • Author(s): Kitadani J, Ojima T, Nakamura M, Hayata K, Katsuda M, Takeuchi A, Tominaga S, Fukuda N, Motobayashi H, Nakai T, Yamaue H.
  • Journal Title: Medicine (Baltimore). Volume: 100 Issue: 4 Pages: e23932-e23932
  • DOI: 10.1097/md.0000000000023932
  • Peer Reviewed / Open Access
• [Journal Article] Single-incision laparoscopic antrectomy for type I gastric neuroendocrine tumor: a case report. (2021)
  • Author(s): Kitadani J, Ojima T, Hayata K, Katsuda M, Tominaga S, Fukuda N, Motobayashi H, Nagano S, Nakamura M, Yamaue H.
  • Journal Title: Surg Case Rep. Volume: 7 Issue: 1 Pages: 15-15
  • DOI: 10.1186/s40792-021-01109-7
  • Peer Reviewed / Open Access
• [Journal Article] Phase 1 Study of Combined Chemotherapy of Nab-Paclitaxel, S-1, and Oxaliplatin for Gastric Cancer with Peritoneal Metastasis (NSOX Study). (2021)
  • Author(s): Nakamura M, Ojima T, Katsuda M, Hayata K, Kitadani J, Nakamori M, Yamaue H.
  • Journal Title: Oncology. Volume: 99 Issue: 1 Pages: 57-61
  • DOI: 10.1159/000509396
  • Peer Reviewed
• [Journal Article] Robotic Double Tract Reconstruction After Proximal Gastrectomy for Gastric Cancer. (2021)
  • Author(s): Ojima T, Nakamura M, Hayata K, Yamaue H.
  • Journal Title: Ann Surg Oncol. Volume: 28 Issue: 3 Pages: 1445-1446
  • DOI: 10.1245/s10434-020-09015-2
  • Peer Reviewed
• [Journal Article] Full robotic Roux-en-Y reconstruction after gastrectomy for gastric cancer: a loop reconstruction technique. (2020)
  • Author(s): Ojima T, Nakamura M, Yamaue H.
  • Journal Title: Updates Surg. Volume: 72 Issue: 4 Pages: 1279-1281
  • DOI: 10.1007/s13304-020-00889-1
  • Peer Reviewed
• [Journal Article] Robotic D2 total gastrectomy with en-mass removal of the spleen and body and tail of the pancreas for locally advanced gastric cancer. (2020)
  • Author(s): Ojima T, Nakamura M, Hayata K, Yamaue H.
  • Journal Title: Surg Oncol. Volume: 35 Pages: 22-23
  • DOI: 10.1016/j.suronc.2020.07.007
  • Peer Reviewed
• [Journal Article] Endoscopic submucosal tunnel dissection versus conventional endoscopic submucosal dissection for early gastric cancers: outcomes of 799 consecutive cases in a single institution. (2020)
  • Author(s): Ojima T, Takifuji K, Nakamura M, Nakamori M, Hayata K, Kitadani J, Yamaue H.
  • Journal Title: Surg Endosc. Volume: 34 Issue: 12 Pages: 5625-5631
  • DOI: 10.1007/s00464-020-07849-1
  • Peer Reviewed
• [Journal Article] Postoperative atrial fibrillation does not impact on overall survival after esophagectomy in patients with thoracic esophageal cancer: results from a randomized, double-blind, placebo-controlled trial. (2020)
  • Author(s): Ojima T, Nakamura M, Hayata K, Kitadani J, Katsuda M, Nakamori M, Takeuchi A, Maruoka S, Fukuda N, Tominaga S, Motobayashi H, Yamaue H.
  • Journal Title: Oncotarget. Volume: 11 Issue: 25 Pages: 2414-2423
  • DOI: 10.18632/oncotarget.27643
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic Limited Resection for Duodenal Gastrointestinal Stromal Tumors. (2020)
  • Author(s): Ojima T, Nakamura M, Hayata K, Kitadani J, Katsuda M, Takeuchi A, Tominaga S, Yamaue H.
  • Journal Title: J Gastrointest Surg. Volume: 24 Issue: 10 Pages: 2404-2408
  • DOI: 10.1007/s11605-020-04692-6
  • Peer Reviewed
• [Journal Article] Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade (2020)
  • Author(s): Mizumoto Y, Hemmi H, Katsuda M, Miyazawa M, Kitahata Y, Miyamoto A, Nakamori M, Ojima T, Matsuda K, Nakamura M, Hayata K, Fukuda-Ohta Y, Sugiyama M, Ohta T, Orimo T, Okura S, Sasaki I, Tamada K, Yamaue H, Kaisho T.
  • Journal Title: British Journal of Cancer Volume: 122 Issue: 8 Pages: 1185-1193
  • DOI: 10.1038/s41416-020-0757-2
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic Roux-en-Y reconstruction using conventional linear stapler in robotic total gastrectomy for gastric cancer. (2019)
  • Author(s): Ojima T, Nakamura M, Hayata K, Yamaue H.
  • Journal Title: Surg Oncol. Volume: 33 Pages: 9-10
  • DOI: 10.1016/j.suronc.2019.12.003
  • Peer Reviewed
• [Presentation] 大腸癌患者iPS細胞由来樹状細胞を用いた がんワクチン療法：前臨床試験 (2023)
  • Author(s): 尾島 敏康 丸岡 慎平 岩本 博光 北谷 純也 山上 裕機
  • Organizer: 第22回日本再生医療学会総会
• [Presentation] Short-term Outcomes of Robotic Gastrectomy vs Laparoscopic Gastrectomy for Patients With Gastric Cancer: A Randomized Clinical Trial (2023)
  • Author(s): Toshiyasu Ojima, Keiji Hayata, Junya Kitadani, Shinta Tominaga, Taro Goda, Masaki Ohi, Hiroki Yamaue, Manabu Kawai
  • Organizer: ASCO-GI 2023
  • Int'l Joint Research
• [Presentation] iPS細胞由来樹状細胞を用いた癌ワクチン療法 (2021)
  • Author(s): 尾島敏康 岩本博光 北谷純也 丸岡慎平 冨永信太 山上裕機
  • Organizer: 第20回日本再生医療学会総会
  • Invited