Investigation of combined immune checkpoint blockade in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous, mostly professional, asbestos exposure in most afflicted patients. Although preventive measures to limit asbestos use and exposure have been around for several decades, the incidence of MPM is still expected to increase over the next decade due to the long latency between asbestos exposure and MPM development. The prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of less than 5%, due to its aggressive nature and the limited effectiveness of any conventional anti-cancer treatment (i.e. chemotherapy, surgery and radiotherapy). The new chemotherapy regimens consisting of a combination of a platinum compound and the folate antimetabolites pemetrexed or raltitrexed have a significant but limited impact on overall survival in MPM. Therefore, new therapeutic strategies are needed to complement the limited armamentarium against MPM. The observation that the immune system can recognize and eliminate tumors is the impetus of the fast-growing research domain of cancer immunotherapy. With the discovery of immune checkpoints, immunotherapy of cancer has entered a new and exciting phase. Clinical studies in a.o. melanoma, renal cell cancer and lung cancer have shown that anti-PD-1 immunotherapy has durable clinical activity, even after treatment cessation, resulting in approval. Also anti-PD-L1 immunotherapy has been approved for treatment of different cancers. PD-1 and PD-L1 expression data in MPM of us and others laid the basis to evaluate their suitability as immunotherapeutic targets also in MPM. Two clinical trials, investigating PD-1 or PD-L1 inhibition in mesothelioma (KEYNOTE-28 and JAVELIN trial, respectively), have already shown promising results with room for improvement. Two other immune checkpoints, being lymphocyte activation gene-3 (LAG-3) and T-cell mucin immunoglobulin-3 (TIM-3), recently gained more interest since they have been described to be associated with T-cell tolerance and exhausted T cells that are infiltrating the tumor micro-environment. Our data on TIM-3 and LAG-3 expression in MPM effusions and on TIM-3 in MPM tissue samples identify both as promising new targets in MPM. Combined targeting of PD-1/PD-L1 with TIM-3 or LAG-3 was highly effective in controlling tumor growth in vivo in different other solid tumor models, providing a rationale to investigate combined blockade also in MPM. Smart combination strategies might improve the antitumor response by interfering with multiple immune escape mechanisms.

Keywords:MESOTHELIOMA

Disciplines:Cancer therapy