ABSTRACT
Malignant pleural mesothelioma (MPM) is a locally aggressive disease related to asbestos exposure with a median survival for untreated patients of 4-8 months. The combination of chemotherapy based on platinum and antifolate is the standard treatment, and the addition of bevacizumab adds two months to median survival. Recently, in first-line treatment, immunotherapy combining nivolumab with ipilimumab has been shown to be superior to chemotherapy in the CheckMate-743 study in terms of overall survival (18.1 months), leading to its approval by the FDA and EMA. The positive results of this study represent a new standard of treatment for patients with MPM; however, not all patients will benefit from immunotherapy treatment. In an effort to improve the selection of patient candidates for immunotherapy for different tumors, biomarkers that have been associated with a greater possibility of response to treatment have been described. MPM is a type of tumor with low mutational load and neo-antigens, making it a relatively non-immunogenic tumor for T cells and possibly less susceptible to responding to immunotherapy. Different retrospective studies have shown that PD-L1 expression occurs in 20-40% of patients and is associated with a poor prognosis; however, the predictive value of PD-L1 in response to immunotherapy has not been confirmed. The purpose of this work is to review the state of the art of MPM treatment in the year 2023, focusing on the efficacy results of first-line or subsequent immunotherapy studies on patients with MPM and possible chemo-immunotherapy combination strategies. Additionally, potential biomarkers of response to immunotherapy will be reviewed, such as histology, PD-L1, lymphocyte populations, and TMB.
ABSTRACT
MPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.
ABSTRACT
BACKGROUND: Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients. METHODS: R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable. RESULTS: A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07-2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46-0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001). CONCLUSIONS: In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy.
