Dendritic Cell-based Immunotherapy Pulsed With Wilms Tumor 1 Peptide and Mucin 1 as an Adjuvant Therapy for Pancreatic Ductal Adenocarcinoma After Curative Resection: A Phase I/IIa Clinical Trial

OBJECT Dendritic cell (DC)-based vaccination is considered a potentially effective therapy against advanced cancer. The authors conducted a Phase I study to investigate the safety and immunomonitoring of Wilms’ tumor 1 (WT1)-pulsed DC vaccination therapy for patients with relapsed malignant glioma. METHODS WT1-pulsed and/or autologous tumor lysate-pulsed DC vaccination therapy was performed in patients with relapsed malignant gliomas. Approximately 1 × 107 to 2 × 107 pulsed DCs loaded with WT1 peptide antigen and/or tumor lysate were intradermally injected into the axillary areas with OK-432, a streptococcal preparation, at 2-week intervals for at least 5–7 sessions (1 course) during an individual chemotherapy regimen. RESULTS Ten patients (3 men, 7 women; age range 24–64 years [median 39 years]) with the following tumors were enrolled: glioblastoma (6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), and anaplastic oligodendroglioma (1). Modified WT1 peptide–pulsed DC vaccine was administered to 7 patients, tumor lysate-pulsed DC vaccine to 2 patients, and both tumor lysate–pulsed and WT1-pulsed DC vaccine to 1 patient. The clinical response was stable disease in 5 patients with WT1-pulsed DC vaccination. In 2 of 5 patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. No serious adverse events occurred except Grade 1–2 erythema at the injection sites. WT1 tetramer analysis detected WT1-reactive cytotoxic T cells after vaccination in patients treated with WT1-pulsed therapy. Positivity for skin reaction at the injection sites was 80% (8 of 10 patients) after the first session, and positivity remained for these 8 patients after the final session. CONCLUSIONS This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas.

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Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2008.12.006 ◽

2009 ◽

Vol 35 (6) ◽

pp. 600-604 ◽

Cited By ~ 169

Author(s):

A. Van den broeck ◽

G. Sergeant ◽

N. Ectors ◽

W. Van Steenbergen ◽

R. Aerts ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Curative Resection ◽

Ductal Adenocarcinoma ◽

Patterns Of Recurrence

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Impact of the Controlling Nutritional Status Score on the Prognosis After Curative Resection of Pancreatic Ductal Adenocarcinoma

Pancreas ◽

10.1097/mpa.0000000000001105 ◽

2018 ◽

Vol 47 (7) ◽

pp. 823-829 ◽

Cited By ~ 11

Author(s):

Yoshiyasu Kato ◽

Suguru Yamada ◽

Masaya Suenaga ◽

Hideki Takami ◽

Yukiko Niwa ◽

...

Keyword(s):

Nutritional Status ◽

Pancreatic Ductal Adenocarcinoma ◽

Curative Resection ◽

Ductal Adenocarcinoma ◽

Status Score

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Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels

Bioscience Reports ◽

10.1042/bsr20200401 ◽

2020 ◽

Vol 40 (7) ◽

Cited By ~ 1

Author(s):

Jiali Du ◽

Jichun Gu ◽

Ji Li

Keyword(s):

Drug Resistance ◽

Clinical Trials ◽

Phase I ◽

Pancreatic Ductal Adenocarcinoma ◽

Solid Tumours ◽

Phase Iii ◽

Ductal Adenocarcinoma ◽

Phase Iii Trials ◽

Exploitation And Exploration ◽

Different Levels

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.

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Repression of MUC1 promotes expansion and suppressive function of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma and breast cancer murine models

10.1101/2020.12.07.415299 ◽

2020 ◽

Author(s):

S. Mahnaz ◽

L. Das Roy ◽

M. Bose ◽

C. De ◽

S. Nath ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathways ◽

Suppressor Cells ◽

Ductal Adenocarcinoma ◽

Myeloid Derived Suppressor Cells ◽

Mucin 1 ◽

Transmembrane Glycoprotein ◽

The Impact

ABSTRACTMyeloid-derived suppressor cells (MDSCs) are immature myeloid cells that are responsible for immunosuppression in tumor microenvironment. Here we report the impact of mucin 1 (MUC1), a transmembrane glycoprotein, on proliferation and functional activity of MDSCs. To determine the role of MUC1 in MDSC phenotype, we analyzed MDSCs derived from wild type (WT) and MUC1-knockout (MUC1KO) mice bearing pancreatic ductal adenocarcinoma KCKO and breast cancer C57MG xenografts. We observed enhanced tumor growth in MUC1KO mice compared to WT mice in both pancreatic KCKO and breast C57MG cancer models due to increased MDSC population and enrichment of Tregs in tumor microenvironment. Our current study shows that knockdown of MUC1 in MDSCs promotes proliferation and immature suppressive phenotype indicated by increased level of iNOS, ARG1 activity and TGF-β secretion under cancer conditions. Increased activity of MDSCs leads to repression of IL-2 and IFN-ɣ production by T-cells. We were able to find that MDSCs from MUC1KO mice have higher levels of c-Myc and activated pSTAT3 as compared to MUC1 WT mice, that are signaling pathways leading to increased survival, proliferation and prevention of maturation. In summary, MUC1 regulates signaling pathways that maintain immunosuppressive properties of MDSCs. Thus, immunotherapy must target only tumor associated MUC1 on epithelial cells and not MUC1 on hematopoietic cells to avoid expansion and suppressive functions of MDSC.

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Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2

Journal of Clinical Oncology ◽

10.1200/jco.18.00089 ◽

2019 ◽

Vol 37 (3) ◽

pp. 230-238 ◽

Cited By ~ 25

Author(s):

Teresa Macarulla ◽

Roberto Pazo-Cid ◽

Carmen Guillén-Ponce ◽

Rafael López ◽

Ruth Vera ◽

...

Keyword(s):

Phase I ◽

Pancreatic Ductal Adenocarcinoma ◽

Phase Ii ◽

Karnofsky Performance Status ◽

Performance Status ◽

Ductal Adenocarcinoma ◽

Tolerability Profile ◽

Ecog Performance Status ◽

Actuarial Survival ◽

Number Of Patients

Purpose Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. Patients and Methods In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. Results Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). Conclusion NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.

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