Long-Term Follow-Up of Mesothelioma Patients Treated with Dendritic Cell Therapy in Three Phase I/II Trials

Our plain-English summary of Long-Term Follow-Up of Mesothelioma Patients Treated with Dendritic Cell Therapy in Three Phase I/II Trials, by D.W. Dumoulin, R. Cornelissen, K. Bezemer, et al (Vaccines, 2021).

The study

• Authors: D.W. Dumoulin, R. Cornelissen, K. Bezemer, S.J. Baart, J.G.J.V. Aerts
• Journal: Vaccines
• Published: 2021;9(5)
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a fatal neoplasm with, if untreated, poor survival of approximately nine months from diagnosis. Until recently, phase II-III immunotherapy trials did not show any significant benefit. The lack of immunotherapy efficacy can be explained by the fact that mesothelioma is a tumor with an "immune desert" phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of DCs, which were ex-vivo cultured, exposed to (tumor-associated) antigens, and subsequently activated, this "immune desert" phenotype might be turned into an "inflamed" phenotype. Three phase I/II studies have been performed and published using activated DCs, which support this concept. We here report on the long-term survival of patients treated with DCs in three phase I/II studies.

Methods: Survival data of the phase I/II trials using DC therapy in MPM patients were obtained and subsequently analyzed. In the first two trials, DCs were loaded with autologous tumor lysate. In the third trial, DCs were loaded with allogeneic mesothelioma tumor cell line lysate.

Results: In the three studies combined, 29 patients with MPM were treated with DC vaccination between 2006 and 2015. At data cut-off, the median OS was 27 months (95% CI: 21-47 months). OS at 2 years was 55.2% (95% CI: 39.7-76.6%), and OS at 5 years was 20.7% (95% CI: 10.1-42.2%).

Conclusions: The long-term survival of DC therapy in MPM in these three trials is promising, which is the basis for the randomized phase II/III DENIM study. This DENIM study is currently enrolling, and the results of which have to be awaited for definite conclusions.

In plain English

This report, by authors at Erasmus MC in Rotterdam, pooled long-term survival data from three earlier phase I/II trials. In them, patients with malignant pleural mesothelioma received dendritic cell vaccination, a treatment using immune cells prepared and activated in the laboratory. In the first two trials the cells were loaded with material from each patient's own tumor. In the third, they were loaded with material from mesothelioma cell lines. In all, 29 patients were treated between 2006 and 2015. Median overall survival was 27 months (95% CI 21 to 47 months). Survival was 55.2% at 2 years (95% CI 39.7 to 76.6%) and 20.7% at 5 years (95% CI 10.1 to 42.2%). Four patients were still alive at 71, 77, 114 and 128 months. All 29 had side effects, mostly mild injection-site reactions and fever. One patient developed a heart muscle problem, which the authors judged probably due to earlier chemotherapy. The authors called the survival promising but said the randomized DENIM trial must be awaited for definite conclusions. They noted that survival was only an exploratory outcome, the trials differed in setup, there was no control group, and later treatments varied.

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: Combined (pooled) survival analysis of three earlier phase I/II treatment trials, with no control group
• Who was studied: 29 patients with malignant pleural mesothelioma (MPM) treated between 2006 and 2015: 10 in trial MM01, 10 in MM02 and 9 in MM03. The authors are affiliated with Erasmus MC, Rotterdam, The Netherlands. The article does not state where the trials were carried out.
• Exposure: The study looked at a treatment, not at asbestos: dendritic cell (DC) vaccination. In MM01 and MM02 the cells were loaded with the patient's own (autologous) tumor lysate after chemotherapy, and MM02 added low-dose cyclophosphamide. In MM03 the cells were loaded with lysate from five mesothelioma cell lines (allogeneic). The article does not report the patients' asbestos exposure.
• Main results:
  • All 29 patients combined: median overall survival 27 months (95% CI 21 to 47 months)
  • All 29 patients combined: overall survival at 2 years 55.2% (95% CI 39.7 to 76.6%), and at 5 years 20.7% (95% CI 10.1 to 42.2%)
  • Four patients were still alive, at 71, 77, 114 and 128 months
  • Trial MM01 (10 patients): median overall survival 15 months, 2-year survival 20% (95% CI 5.8 to 69.1%), 5-year survival 10.0% (95% CI 1.6 to 64.2%)
  • Trial MM02 (10 patients): median overall survival 26 months, 2-year survival 60% (95% CI 36.2 to 99.5%), 5-year survival 30.0% (95% CI 11.6 to 77.3%)
  • Trial MM03 (9 patients): median overall survival 31 months, 2-year survival 88.9% (95% CI 70.6 to 100%). The 5-year survival is given as 22.0% in the text and 22.2% in Table 2 (95% CI 6.6 to 75.4%).
  • Side effects occurred in all 29 patients and were mostly mild. The most common were local skin reactions at the injection site (29 of 29) and fever (21 of 29, 72%).
  • One patient developed cardiomyopathy 18 months after DC therapy, the only grade 3 to 4 event. The authors said it was probably due to previous chemotherapy and could not directly be linked to the vaccination.
• The authors' conclusion: The authors concluded that long-term survival after DC therapy in the three trials was promising, but that results of the randomized phase II/III DENIM study must be awaited for definite conclusions.
• Limitations the authors state:
  • The trials' primary outcomes were safety and feasibility; overall survival was only an exploratory outcome
  • The three trials had different setups, so combining their outcomes should be approached with caution
  • There was no control group, and survival in mesothelioma is known to vary, with some long-term survivors
  • Treatment after disease progression varied over the years. Eight of nine patients in the last trial received immune checkpoint inhibitor therapy at some point, and whether this explains the survival is unknown.
  • Only a minority of screened patients could take part in the first two trials, because not enough viable tumor cells could be obtained

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Neoplasm, Immunotherapy.

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• 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)
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