Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccine
Background A chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy was observed to modulate the tumor microenvironment (TME) to an immunostimulatory state, resulting in conversion surgery in seven out of nine...
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BMJ Publishing Group
2025-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/7/e011426.full |
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| author | Nobuhiro Sato Shigetaka Shimodaira Masayuki Saruta Yoko Shimizu Shigeo Koido Junichi Taguchi Masamori Shimabuku Tuuse Bito Zensho Ito Kan Uchiyama Toshifumi Ohkusa Haruo Sugiyama Soyoko Morimoto Yusuke Oji Yoshihiro Oka Masaki Ito |
| author_facet | Nobuhiro Sato Shigetaka Shimodaira Masayuki Saruta Yoko Shimizu Shigeo Koido Junichi Taguchi Masamori Shimabuku Tuuse Bito Zensho Ito Kan Uchiyama Toshifumi Ohkusa Haruo Sugiyama Soyoko Morimoto Yusuke Oji Yoshihiro Oka Masaki Ito |
| author_sort | Nobuhiro Sato |
| collection | DOAJ |
| description | Background A chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy was observed to modulate the tumor microenvironment (TME) to an immunostimulatory state, resulting in conversion surgery in seven out of nine patients with unresectable pancreatic ductal adenocarcinoma (UR-PDAC).Methods Understanding WT1-specific immunity and the tumor mutational burden is important for predicting the efficacy of WT1-targeted chemoimmunotherapy. Therefore, the memory CD8+T cell subpopulations in WT1-specific cytotoxic T lymphocytes (WT1-CTLs), titers of antibodies against the WT1 epitopes, infiltration of CD103+tissue-resident memory T cells and CD20+cells in the pancreatic TME, gene mutations in plasma circulating tumor DNA (ctDNA) obtained via liquid biopsy, and PDAC cell characteristics were evaluated.Results Prior to treatment, patients with a relatively low number of WT1-specific CD8+naive T (Tn) cells, high levels of WT1-specific IgM antibodies, no mutations in any key genes (KRAS and TP53) in plasma ctDNA that were different in each patient (ie, neoantigens), and low levels of programmed death-ligand 1 expression in PDAC cells presented a markedly superior prognosis compared with patients with alternative patterns. Administration of WT1-targeted chemoimmunotherapy resulted in a significant increase in the proportion of circulating WT1-specific CD8+central memory T (Tcm) cells in super-responders (SRs: progression-free survival (PFS)>median) compared with non-super-responders (NSRs: PFS≤median). Moreover, the ratio of Tcm to terminally differentiated effector memory T cells in WT1-CTLs was greater in SRs than in NSRs after 15 vaccinations. In patients harboring at least one mutated ctDNA, the frequency of each ctDNA mutant allele significantly decreased after WT1-targeted chemoimmunotherapy. In addition, one SR showed remarkably high infiltration of CD103+ or CD20+ cells in the pancreatic TME; however, there was no association between these cell densities and clinical outcomes.Conclusions In patients with UR-PDAC who exhibited spontaneous activation of WT1-specific cellular and humoral immunity prior to treatment, endogenous WT1-specific CD8+Tn cells were engineered into WT1-specific memory CD8+cells via WT1-targeted chemoimmunotherapy, resulting in superior therapeutic effects. WT1-targeted chemoimmunotherapy also induced neoantigen-specific immune responses via epitope spreading, leading to the elimination of neoantigen-expressing PDAC cells and favorable clinical outcomes.Trial registration number jRCTc030190195. |
| format | Article |
| id | doaj-art-0c78e6960b7247e796bb20aaa4bdacd8 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-0c78e6960b7247e796bb20aaa4bdacd82025-08-20T03:32:11ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-07-0113710.1136/jitc-2024-011426Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccineNobuhiro Sato0Shigetaka Shimodaira1Masayuki Saruta2Yoko Shimizu3Shigeo Koido4Junichi Taguchi5Masamori Shimabuku6Tuuse Bito7Zensho Ito8Kan Uchiyama9Toshifumi Ohkusa10Haruo Sugiyama11Soyoko Morimoto12Yusuke Oji13Yoshihiro Oka14Masaki Ito158 Department of Microbiota Research, Juntendo University School of Medicine Graduate School of Medicine, Bunkyo, Tokyo, Japan9 Department of Regenerative Medicine, Kanazawa Medical University, Kahoku, Ishikawa, Japan7 Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Minato, Tokyo, Japan3 Tokyo Midtown Clinic, Minato, Tokyo, Japan1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan3 Tokyo Midtown Clinic, Minato, Tokyo, Japan3 Tokyo Midtown Clinic, Minato, Tokyo, Japan4 Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Chiba, Japan1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University Kashiwa Hospital, Kashiwa, Chiba, Japan10 Department of Cancer Immunology, The University of Osaka Graduate School of Medicine, Suita, Osaka, Japan5 Department of Cancer Stem Cell Biology, The University of Osaka Graduate School of Medicine, Suita, Osaka, Japan6 Department of Clinical Laboratory and Biomedical Sciences, The University of Osaka Graduate School of Medicine, Suita, Osaka, Japan5 Department of Cancer Stem Cell Biology, The University of Osaka Graduate School of Medicine, Suita, Osaka, Japan4 Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Chiba, JapanBackground A chemoimmunotherapy regimen consisting of a novel Wilms’ tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy was observed to modulate the tumor microenvironment (TME) to an immunostimulatory state, resulting in conversion surgery in seven out of nine patients with unresectable pancreatic ductal adenocarcinoma (UR-PDAC).Methods Understanding WT1-specific immunity and the tumor mutational burden is important for predicting the efficacy of WT1-targeted chemoimmunotherapy. Therefore, the memory CD8+T cell subpopulations in WT1-specific cytotoxic T lymphocytes (WT1-CTLs), titers of antibodies against the WT1 epitopes, infiltration of CD103+tissue-resident memory T cells and CD20+cells in the pancreatic TME, gene mutations in plasma circulating tumor DNA (ctDNA) obtained via liquid biopsy, and PDAC cell characteristics were evaluated.Results Prior to treatment, patients with a relatively low number of WT1-specific CD8+naive T (Tn) cells, high levels of WT1-specific IgM antibodies, no mutations in any key genes (KRAS and TP53) in plasma ctDNA that were different in each patient (ie, neoantigens), and low levels of programmed death-ligand 1 expression in PDAC cells presented a markedly superior prognosis compared with patients with alternative patterns. Administration of WT1-targeted chemoimmunotherapy resulted in a significant increase in the proportion of circulating WT1-specific CD8+central memory T (Tcm) cells in super-responders (SRs: progression-free survival (PFS)>median) compared with non-super-responders (NSRs: PFS≤median). Moreover, the ratio of Tcm to terminally differentiated effector memory T cells in WT1-CTLs was greater in SRs than in NSRs after 15 vaccinations. In patients harboring at least one mutated ctDNA, the frequency of each ctDNA mutant allele significantly decreased after WT1-targeted chemoimmunotherapy. In addition, one SR showed remarkably high infiltration of CD103+ or CD20+ cells in the pancreatic TME; however, there was no association between these cell densities and clinical outcomes.Conclusions In patients with UR-PDAC who exhibited spontaneous activation of WT1-specific cellular and humoral immunity prior to treatment, endogenous WT1-specific CD8+Tn cells were engineered into WT1-specific memory CD8+cells via WT1-targeted chemoimmunotherapy, resulting in superior therapeutic effects. WT1-targeted chemoimmunotherapy also induced neoantigen-specific immune responses via epitope spreading, leading to the elimination of neoantigen-expressing PDAC cells and favorable clinical outcomes.Trial registration number jRCTc030190195.https://jitc.bmj.com/content/13/7/e011426.full |
| spellingShingle | Nobuhiro Sato Shigetaka Shimodaira Masayuki Saruta Yoko Shimizu Shigeo Koido Junichi Taguchi Masamori Shimabuku Tuuse Bito Zensho Ito Kan Uchiyama Toshifumi Ohkusa Haruo Sugiyama Soyoko Morimoto Yusuke Oji Yoshihiro Oka Masaki Ito Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccine Journal for ImmunoTherapy of Cancer |
| title | Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccine |
| title_full | Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccine |
| title_fullStr | Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccine |
| title_full_unstemmed | Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccine |
| title_short | Predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional Wilms’ tumor 1 (WT1) peptide cocktail-pulsed dendritic cell vaccine |
| title_sort | predictors of patients with advanced pancreatic cancer undergoing conversion surgery via chemoimmunotherapy with a multifunctional wilms tumor 1 wt1 peptide cocktail pulsed dendritic cell vaccine |
| url | https://jitc.bmj.com/content/13/7/e011426.full |
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