Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial

Our plain-English summary of Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial, by M.V. Dietz, K.L.A. Quintelier, J.P. van Kooten, et al (Journal for Immunotherapy of Cancer, 2023).

The study

• Authors: M.V. Dietz, K.L.A. Quintelier, J.P. van Kooten, N.L. de Boer, M. Vink, A.R.M. Brandt-Kerkhof, C. Verhoef, Y. Saeys, J.G.J.V. Aerts, M. Willemsen, S. Van Gassen, E.V.E. Madsen
• Journal: Journal for Immunotherapy of Cancer
• Published: 2023;11(8)
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant peritoneal mesothelioma (MPM) is an aggressive malignancy with a poor prognosis. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival outcomes, but recurrence rates remain high. Dendritic cell-based immunotherapy (DCBI) showed promising results in patients with pleural mesothelioma. The primary aim of this trial was to determine feasibility of adjuvant DCBI after CRS-HIPEC.

Methods: This open-label, single-center, phase II clinical trial, performed in the Erasmus MC Cancer Institute Rotterdam, the Netherlands, included patients with epithelioid MPM. 4-6 weeks before CRS-HIPEC leukapheresis was performed. 8-10 weeks after surgery, DCBI was administered three times biweekly. Feasibility was defined as administration of at least three adjuvant vaccinations in 75% of patients. Comprehensive immune cell profiling was performed on peripheral blood samples prior to and during treatment.

Results: All patients who received CRS-HIPEC (n=16) were successfully treated with adjuvant DCBI. No severe toxicity related to DCBI was observed. Median progression-free survival (PFS) was 12 months (IQR 5-23) and median overall survival was not reached. DCBI was associated with increased proliferation of circulating natural killer cells and CD4+ T-helper (Th) cells. Co-stimulatory molecules, including ICOS, HLA-DR, and CD28 were upregulated predominantly on memory or proliferating Th-cells and minimally on CD8+ cytotoxic T-lymphocytes (CTLs) after treatment. However, an increase in CD8+ terminally differentiated effector memory (Temra) cells positively correlated with PFS, whereas co-expression of ICOS and Ki67 on CTLs trended towards a positive correlation.

Conclusions: Adjuvant DCBI after CRS-HIPEC in patients with MPM was feasible and safe, and showed promising survival outcomes. DCBI had an immune modulatory effect on lymphoid cells and induced memory T-cell activation. Moreover, an increase of CD8+ Temra cells was more pronounced in patients with longer PFS. These data provide rationale for future combination treatment strategies.

Trial Registration Number: NTR7060; Dutch Trial Register (NTR).

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This single-arm phase II trial took place at Erasmus MC Cancer Institute, Rotterdam, the Netherlands. It tested whether a dendritic cell vaccine, MesoPher, could be given after surgery with heated intraperitoneal chemotherapy (CRS-HIPEC) for epithelioid malignant peritoneal mesothelioma. Eighteen patients were enrolled between March 2018 and September 2022. Two did not have surgery. The other 16 were to get three doses two weeks apart from 8 to 10 weeks after surgery, then boosters at 3 and 6 months. Three had joined the trial only after surgery, and five did not receive all five doses because their disease progressed. Two of the 18 patients had a known history of asbestos exposure. All 16 received the first three doses, which was the trial's feasibility measure. No serious vaccine-related adverse events were reported, and none above grade 2. Median progression-free survival was 12 months (IQR 5 to 23), and median overall survival could not be determined. Blood tests showed increased proliferation of natural killer cells and helper T cells. The authors concluded the treatment was feasible and safe. They noted that the small sample and limited follow-up allowed no robust statements about its effect on survival.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Open-label, single-arm, single-center phase II clinical trial of adjuvant dendritic cell-based immunotherapy (MesoPher) after CRS-HIPEC
• Who was studied: 18 patients with epithelioid malignant peritoneal mesothelioma enrolled at Erasmus MC Cancer Institute, Rotterdam, the Netherlands, between March 2018 and September 2022. Of these, 16 underwent CRS-HIPEC and received the vaccine.
• Exposure: The intervention studied was autologous dendritic cell vaccination (MesoPher). It was planned as three biweekly doses starting 8 to 10 weeks after surgery, with boosters at 3 and 6 months. Asbestos exposure was not the subject of the study; it was recorded only as a patient characteristic.
• Main results:
  • All 16 patients who underwent CRS-HIPEC received the first three vaccinations according to protocol.
  • Five of the 16 patients (31.3%) had progressive disease at the first response evaluation and so did not receive all five vaccinations.
  • Three patients were enrolled after their CRS-HIPEC had already been performed, at 28, 5 and 7 weeks after surgery.
  • No patient had a serious adverse event or suspected unexpected serious adverse reaction related to the vaccination, and no vaccine-related adverse events above CTCAE grade 2 were reported.
  • The most common infusion-related reactions among the 16 vaccinated patients were cold chills (63%), fever (56%), fatigue (50%) and malaise (38%).
  • Median progression-free survival for all 16 patients was 12 months (IQR 5 to 23). Six of the 16 had died at database lock, so median overall survival could not be determined.
  • Median progression-free survival was 20 months for patients with complete cytoreduction (n=10) and 4 months for patients with incomplete cytoreduction (n=6).
  • Vaccination significantly increased the proportions of proliferating (Ki67+) natural killer cells and T-helper cells in the blood.
  • An increase in CD8+ terminally differentiated effector memory (Temra) cells after one vaccination positively correlated with progression-free survival.
  • Two of the 18 enrolled patients had a known history of asbestos exposure, and 2 carried a BAP1 germline mutation.
• The authors' conclusion: The authors concluded that adjuvant dendritic cell-based immunotherapy after CRS-HIPEC in patients with malignant peritoneal mesothelioma was feasible and safe and showed promising survival outcomes. They called for future research on its effect on survival and on combination treatments.
• Limitations the authors state:
  • Small sample size and limited follow-up time, so robust statements about the effect on survival cannot be made
  • Protocol violations: three patients were enrolled after their CRS-HIPEC had already been performed
  • Immune measurements were taken on multiple days, which introduced batch effects in the computational analysis
  • No tumor tissue was available after treatment, so it is unknown whether T-cell activation in the blood was matched by immune cells entering the tumor

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Immunotherapy, Cytoreductive Surgery, HIPEC, Peritoneal Mesothelioma, Clinical Trial, Prognosis, Pleural Mesothelioma, Epithelioid.

Related studies

• Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial — N.L. de Boer, J.P. van Kooten, et al. (2019)
• Phase II Trial of Adjuvant Dendritic Cell Vaccine in Combination with Celecoxib, Interferon-α, and Rintatolimod in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases — R. Ramanathan, H. Choudry, et al. (2021)
• Assessing morbidity, mortality, and survival in patients with peritoneal carcinomatosis undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy — J.S.A. Vallejo, F.L. Queiroz, et al. (2023)
• Clinical course for patients with peritoneal carcinomatosis excluded from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy — A.P. Rodt, R.O. Svarrer, et al. (2013)
• Safe performance of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with HIV infection — A. Coghill, J. Sanchez, et al. (2022)
• Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: a systematic review and meta-analysis — J.H. Helm, J.T. Miura, et al. (2015)

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