Combination of PD-1/PD-L1 checkpoint inhibition and dendritic cell therapy in mice models and in patients with mesothelioma

Our plain-English summary of Combination of PD-1/PD-L1 checkpoint inhibition and dendritic cell therapy in mice models and in patients with mesothelioma, by M. van Gulijk, B. Belderbos, D. Dumoulin, et al (International Journal of Cancer, 2023).

The study

• Authors: M. van Gulijk, B. Belderbos, D. Dumoulin, R. Cornelissen, K. Bezemer, L. Klaase, F. Dammeijer, J. Aerts
• Journal: International Journal of Cancer
• Published: 2023;152(7):1438-1443
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Immunotherapy with anti-PD1/PD-L1 is effective in only a subgroup of patients with malignant pleural mesothelioma (MPM). We investigated the efficacy of a combination of anti-PD1/PD-L1 and dendritic cell (DC) therapy to optimally induce effective anti-tumor immunity in MPM in both humans and mice. Data of nine MPM patients treated with DC therapy and sequential anti-PD1 treatment were collected and analyzed for progression-free survival (PFS) and overall survival (OS). Survival and T-cell responses were monitored in AC29 mesothelioma-bearing mice treated concurrently with the combination therapy; additionally, the role of the tumor-draining lymph node (TDLN) was investigated. The combination therapy resulted in a median OS and PFS of 17.7 and 8.0 months, respectively. Grade 3 to 4 treatment-related adverse events had not been reported. Survival of the mesothelioma-bearing mice treated with the combination therapy was longer than that of untreated mice, and coincided with improved T-cell activation in peripheral blood and less T-cell exhaustion in end stage tumors. Comparable results were obtained when solely the TDLN was targeted. We concluded that this combination therapy is safe and shows promising OS and PFS. The murine data support that PD-L1 treatment may reinvigorate the T-cell responses induced by DC therapy, which may primarily be the result of TDLN targeting.

© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

In plain English

This short report from Erasmus Medical Center in Rotterdam, the Netherlands, combined patient records with mouse experiments. It did not study asbestos exposure. The authors collected data on nine patients with malignant pleural mesothelioma who first had dendritic cell therapy, made from their own immune cells loaded with tumor material. After their disease progressed, they received the checkpoint drugs nivolumab (seven patients, one also given ipilimumab) or pembrolizumab (two patients). Measured from the start of checkpoint treatment, median progression-free survival was 8.0 months and median overall survival was 17.7 months. Three patients had partial responses, five had stable disease and one had progressive disease. No grade 3 or 4 side effects were found. In mice with AC29 mesothelioma tumors, dendritic cell therapy and anti-PD-L1 given at the same time led to longer survival than no treatment and to less-exhausted T cells. Blocking PD-L1 only in the tumor-draining lymph node gave similar results. The authors concluded that the combination could be promising. They cautioned about possible bias in patient selection.

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: Short report combining retrospectively collected data from nine patients with mouse experiments
• Who was studied: Nine patients with histologically proven malignant pleural mesothelioma treated at Erasmus MC, Rotterdam (final data check November 19, 2021). Female CBA/J mice bearing AC29 mesothelioma tumors (survival experiment: n = 7 per group, total n = 35).
• Exposure: No asbestos exposure was studied. The treatments were as follows. Patients received dendritic cell therapy (autologous monocyte-derived DCs loaded with allogeneic, n = 8, or autologous, n = 1, tumor lysate). After progression they received anti-PD-1 therapy: nivolumab 3 mg/kg every 2 weeks or pembrolizumab 2 mg/kg every 3 weeks, and one patient received nivolumab plus ipilimumab. Mice received DC therapy given at the same time as anti-PD-L1 antibody, either a systemic 200 μg dose or a low 2.5 μg dose aimed at the tumor-draining lymph node.
• Main results:
  • In the nine patients, measured from the start of checkpoint blockade, median progression-free survival was 8.0 months and median overall survival was 17.7 months.
  • Of the nine patients, three had partial responses, five had stable disease and one had progressive disease, giving an objective response rate of 33%.
  • At 6 months, five of the nine patients (55.6%) showed disease control.
  • No grade 3 or 4 adverse events were found in the patients.
  • In mesothelioma-bearing mice, DC therapy combined at the same time with anti-PD-L1 led to longer survival than in untreated mice.
  • In the mice, combination treatment most strongly decreased TOX, a driver of T-cell exhaustion, on tumor-infiltrating T cells, indicating less-exhausted T cells.
  • In the mice, blocking PD-L1 only in the tumor-draining lymph nodes gave survival and immune changes similar to systemic anti-PD-L1 treatment.
• The authors' conclusion: The authors concluded that their patient and mouse data indicate the combination of DC therapy and anti-PD-1/PD-L1 could be a promising treatment for malignant pleural mesothelioma, as it was found feasible and safe and showed clinical efficacy.
• Limitations the authors state:
  • Possible bias in patient selection calls for caution in interpreting the patient results.
  • No biopsies were taken from patients before and after treatment, so the PD-L1 increase seen in mice could not be investigated in patients.
  • Because tumors grew rapidly, the mouse experiments could not include an arm in which DC therapy and anti-PD-L1 were given one after the other, as in the patients.
  • Patients received drugs blocking PD-1, while mice received antibodies blocking its ligand PD-L1, which may have different immune effects.

Topics

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

Medical terms in this study, explained in our Lexicon: PD-1/PD-L1, Mesothelioma, Immunotherapy, PD-L1, Pleural Mesothelioma, Progression-Free Survival, Overall Survival.

Related studies

• Autologous Dendritic Cell Therapy in Mesothelioma Patients Enhances Frequencies of Peripheral CD4 T Cells Expressing HLA-DR, PD-1, or ICOS — P.L. de Goeje, Y. Klaver, et al. (2018)
• 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)
• Anti-cancer therapy using dendritic cells and apoptotic tumour cells: pre-clinical data in human mesothelioma and acute myeloid leukaemia — M. Grégoire, C. Ligeza-Poisson, et al. (2003)
• Immune checkpoint therapy of mesothelioma: Pre-clinical bases and clinical evidences — L. Calabrò, G.L. Ceresoli, et al. (2017)
• Long-Term Follow-Up of Mesothelioma Patients Treated with Dendritic Cell Therapy in Three Phase I/II Trials — D.W. Dumoulin, R. Cornelissen, et al. (2021)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)

Browse more research in International Journal of Cancer, or return to medical research.