The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3

Our plain-English summary of The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3, by E. Marcq, J.R.M. Van Audenaerde, J. De Waele, et al (Cancers, 2021).

The study

• Authors: E. Marcq, J.R.M. Van Audenaerde, J. De Waele, C. Merlin, P. Pauwels, J.P. van Meerbeeck, S.A. Fisher, E.L.J. Smits
• Journal: Cancers
• Published: 2021;13(2)
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9-12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.

In plain English

This was a laboratory study with an animal experiment. It did not study asbestos exposure. The authors tested antibodies that block the immune checkpoints PD-1, PD-L1, TIM-3 and LAG-3, alone and in pairs, against malignant pleural mesothelioma. First, three human mesothelioma cell lines were grown with blood immune cells from healthy donors. Blocking PD-1 or PD-L1, alone or with TIM-3 blockade, gave the highest levels of several immune signalling molecules, though not all differences were statistically significant. Next, female mice with an implanted mouse mesothelioma tumor (AB1-HA) received three antibody doses. Compared with a PBS control group, anti PD-L1 alone and anti PD-L1 plus anti LAG-3 delayed tumor growth, but not significantly. Both gave a statistically significant survival benefit (p = 0.03 and p = 0.003). The two treatments did not differ significantly from each other. The authors concluded that these two treatments gave the best responses in the mouse model. They noted limits: the human cells were from unmatched donors, the tumors were placed under the skin rather than in the chest, and larger studies are needed.

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: Laboratory (in vitro) study of human mesothelioma cell lines grown with donor immune cells, followed by an animal experiment in mice
• Who was studied: Three human malignant pleural mesothelioma cell lines (two epithelioid, one sarcomatoid), each grown with blood immune cells (PBMC) from three different healthy donors. Female BALB/cJ mice, 6 to 8 weeks old, injected under the skin with the mouse mesothelioma cell line AB1-HA at the University of Antwerp, Belgium. The survival figure gives n = 18, pooled data from three independent experiments.
• Exposure: No asbestos exposure was studied. The exposure was treatment with immune checkpoint blocking antibodies (anti PD-1, anti PD-L1, anti TIM-3, anti LAG-3), alone or in pairs. In the mice, each dose was 200 µg, given every third day for three doses.
• Main results:
  • In the human cell co-cultures, PD-1 or PD-L1 blockade, alone or combined with TIM-3 blockade, produced the highest concentrations of IFN-gamma, granzyme B, IL-2, IL-10 and TNF-alpha.
  • Not all of these in vitro differences between treatments were statistically significant. For IFN-gamma, significant differences were found only for the NCI-H2818 cell line.
  • PD-L1 on donor immune cells increased significantly after co-culture with two of the three mesothelioma cell lines. The same trend was seen with the third.
  • In the mice, anti PD-L1 alone and anti PD-L1 plus anti LAG-3 delayed tumor growth compared with the PBS control group, but the difference was not statistically significant.
  • In the mice, survival was significantly longer than in the PBS control group for anti PD-L1 alone (p = 0.03) and for anti PD-L1 plus anti LAG-3 (p = 0.003).
  • The survival of mice given anti PD-L1 alone and of mice given anti PD-L1 plus anti LAG-3 did not differ significantly. The authors suggested that the benefit of the combination was mainly due to PD-L1 blockade.
  • The authors reported that in the mice TIM-3 blockade was associated with increased tumor growth and worse survival compared with the control group.
• The authors' conclusion: The authors concluded that in the AB1-HA mouse mesothelioma model the best responses were seen with PD-L1 blockade alone and with PD-L1 plus LAG-3 blockade. They said there is still room for improvement and planned to adjust the dosing schedule.
• Limitations the authors state:
  • The in vitro co-cultures used tumor cells and immune cells from different people (an allogeneic setting), because patient-matched cells were scarce.
  • The mouse tumors were placed under the skin (subcutaneous) rather than at the site where the disease occurs (an orthotopic model).
  • Survival data alone could not show whether the combination worked better than PD-L1 blockade alone. Further research with a larger sample size is needed.
  • The immune checkpoint expression measurements are a snapshot in time, and this expression is known to change.

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Prognosis, Median Overall Survival, Cytokine.

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• Recent Advances of Immune Checkpoint Inhibition and Potential for (Combined) TIGIT Blockade as a New Strategy for Malignant Pleural Mesothelioma — S. Rovers, A. Janssens, et al. (2022)
• Taking a retrospective look at asbestos-related thoracic disease produces interesting results — E.B. Gottschall (2010)
• Is it useful to combine sputum cytology and low-dose spiral computed tomography for early detection of lung cancer in formerly asbestos-exposed power industry workers? — M.K. Felten, L. Knoll, et al. (2014)
• Malignant mesothelioma clinical trial combines immunotherapy drugs — M.S. Chatwal, T. Tanvetyanon (2018)
• Combination immune checkpoint blockade as an effective therapy for mesothelioma — V.S. Fear, C. Tilsed, et al. (2018)
• Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations — N. Principe, W.J. Aston, et al. (2022)

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