Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer
Background We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced...
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| Language: | English |
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BMJ Publishing Group
2024-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/10/e009765.full |
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| author | Machi Suka Hiroyuki Yanagisawa Nobuhiro Sato Shigetaka Shimodaira Masayuki Saruta Shigeo Koido Junichi Taguchi Masamori Shimabuku Shin Kan Tuuse Bito Takeyuki Misawa Zensho Ito Kan Uchiyama Shintaro Tsukinaga Toshifumi Ohkusa Haruo Sugiyama |
| author_facet | Machi Suka Hiroyuki Yanagisawa Nobuhiro Sato Shigetaka Shimodaira Masayuki Saruta Shigeo Koido Junichi Taguchi Masamori Shimabuku Shin Kan Tuuse Bito Takeyuki Misawa Zensho Ito Kan Uchiyama Shintaro Tsukinaga Toshifumi Ohkusa Haruo Sugiyama |
| author_sort | Machi Suka |
| collection | DOAJ |
| description | Background We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment.Methods Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02.Results The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients.Conclusions Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1).Trial registration number jRCTc030190195. |
| format | Article |
| id | doaj-art-3756c5f4da2747fd83b90f8049ea096a |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3756c5f4da2747fd83b90f8049ea096a2025-08-20T02:56:15ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-10-01121010.1136/jitc-2024-009765Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancerMachi Suka0Hiroyuki Yanagisawa1Nobuhiro Sato2Shigetaka Shimodaira3Masayuki Saruta4Shigeo Koido5Junichi Taguchi6Masamori Shimabuku7Shin Kan8Tuuse Bito9Takeyuki Misawa10Zensho Ito11Kan Uchiyama12Shintaro Tsukinaga13Toshifumi Ohkusa14Haruo Sugiyama15Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Minato-ku, JapanDepartment of Public Health and Environmental Medicine, The Jikei University School of Medicine, Minato-ku, JapanDepartment of Microbiota Research, Juntendo University, Bunkyo-ku, JapanRegenerative Medicine, Kanazawa Medical University, Kahoku, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Minato-ku, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, JapanTokyo Midtown Clinic, Minato-ku, JapanTokyo Midtown Clinic, Minato-ku, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, JapanDepartment of Surgery, The Jikei University Kashiwa Hospital, Kashiwa, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, JapanDepartment of Endoscopy, The Jikei University Kashiwa Hospital, Kashiwa, JapanDivision of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, JapanDepartment of Functional Diagnostic Science, Osaka University, Suita, JapanBackground We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment.Methods Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02.Results The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients.Conclusions Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1).Trial registration number jRCTc030190195.https://jitc.bmj.com/content/12/10/e009765.full |
| spellingShingle | Machi Suka Hiroyuki Yanagisawa Nobuhiro Sato Shigetaka Shimodaira Masayuki Saruta Shigeo Koido Junichi Taguchi Masamori Shimabuku Shin Kan Tuuse Bito Takeyuki Misawa Zensho Ito Kan Uchiyama Shintaro Tsukinaga Toshifumi Ohkusa Haruo Sugiyama Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer Journal for ImmunoTherapy of Cancer |
| title | Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer |
| title_full | Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer |
| title_fullStr | Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer |
| title_full_unstemmed | Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer |
| title_short | Dendritic cells pulsed with multifunctional Wilms’ tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer |
| title_sort | dendritic cells pulsed with multifunctional wilms tumor 1 wt1 peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer |
| url | https://jitc.bmj.com/content/12/10/e009765.full |
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