Advances in Immunotherapy of Malignant Pleural Mesothelioma

Liao, Dongying; Yu, Yongchao; Mei, Qingyun; Wang, Ziwei; Li, Xiaojiang; Jia, Yulin; Kong, Fanming

doi:10.2147/ott.s317434

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…Conventional treatment for MPM is a combination therapy of cisplatin plus pemetrexed (3)(4)(5). In 2020, a combination of anti-PD-1 mAb nivolumab plus anti-CTLA-4 mAb ipilimumab was approved by the U.S. Food and Drug Administration (FDA) as a first-line therapy for unresectable MPM (7,15,16). Whereas initial promising results of mAb-based therapy have changed the landscape of MPM treatment, the efficacy is limited to a certain subset of patients, indicating an urgent need to establish biomarkers for patient selection (17)(18)(19)(20)(21)(22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma

et al. 2023

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IntroductionMalignant pleural mesothelioma (MPM) is a rare and highly aggressive thoracic tumor with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors exhibit a promising effect in some patients with unresectable MPM in clinical trials, the majority of MPM patients show only modest response rates to the currently available treatments. It is thus imperative to develop novel and innovative therapeutic modalities for MPM, including immune effector cell-based therapies.Methodsγδ T cells were expanded using tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino) ethylidene-1,1-bisphosphonate (PTA) and interleukin-2, and the therapeutic potential of γδ T cells was examined through analyzing cell surface markers and cellular cytotoxicity against MPM in vitro using a europium chelate-based time-resolved fluorescence assay system and a luciferase-based luminescence assay system.Results and discussionWe successfully expanded γδ T cells from peripheral blood mononuclear cells of healthy donors and MPM patients. γδ T cells expressed natural killer receptors such as NKG2D and DNAM-1 and exhibited a moderate level of cytotoxicity to MPM cells in the absence of antigens. The inclusion of PTA, (E)-4-hydroxy-3- methylbut-2-enyl diphosphate (HMBPP) or zoledronic acid (ZOL) induced a TCR-dependent cytotoxicity in γδ T cells and secreted interferon-γ (IFN-γ). In addition, γδ T cells expressing CD16 exhibited a significant level of cytotoxicity against MPM cells in the presence of an anti-epidermal growth factor receptor (EGFR) mAb, at lower concentrations than in clinical settings, whereas a detectable level of IFN-γ was not produced. Taken together, γδ T cells showed cytotoxic activity against MPM in three distinct mechanisms through NK receptors, TCRs and CD16. Since major histocompatibility complex (MHC) molecules are not involved in the recognition, both autologous and allogeneic γδ T cells could be used for the development of γδ T cell-based adoptive immunotherapy for MPM.

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Section: Discussionmentioning

confidence: 99%

Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma

et al. 2023

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“…Checkpoint therapy has currently become available as first-line therapy for patients with unresectable malignant mesothelioma; however, response rates are still limited (45). To evaluate the potential of RPE-mIL2 to increase the efficacy of checkpoint inhibitors, we conducted a combination study with RPE-mIL2 and aPD1 treatment.…”

Section: Rpe-mil2 In Combination With Apd1 Checkpoint Therapy Eradica...mentioning

confidence: 99%

Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors

Nash

Aghlara-Fotovat

Castillio

et al. 2022

Clinical Cancer Research

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Purpose: Interleukin-2 (IL-2) immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL-2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. Experimental Design: We evaluated the therapeutic efficacy of IL-2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. Results: IL-2 cytokine factories enabled 150x higher IL-2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after one week of monotherapy treatment, and 7/7 of animals exhibited tumor eradication without recurrence when IL-2 cytokine factories were combined with aPD1. Further, CyTOF analysis showed an increase in CD69+CD44+ and CCD69-CD44+CD62L+ T cells, reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. Conclusion: IL-2 cytokine factories led to the eradication of aggressive mouse MM tumors, protection from tumor recurrence, and increased the therapeutic efficacy of anti-PD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL-2-based delivery system.

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“…The overall incidence of treatment-related adverse events adjusted for exposure in nivolumab-ipilimumab group is lower than that in chemotherapy group (10). According to the results, nivolumab plus ipilimumab has been approved by the FDA to treat the unresectable MPM as a first-line therapy in October 2020 (11).…”

Section: Introductionmentioning

confidence: 99%

Cost-effectiveness of nivolumab plus ipilimumab as first-line treatment for American patients with unresectable malignant pleural mesothelioma

Tang

et al. 2022

Front. Public Health

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BackgroundThe treatment paradigm of unresectable malignant pleural mesothelioma (MPM) has changed in recent years. Checkmate 743 demonstrate that nivolumab plus ipilimumab showed good clinical benefits compared with chemotherapy in the treatment of MPM. The study is aim to evaluate the cost-effectiveness of Nivolumab plus ipilimumab vs. platinum plus chemotherapy for the first-line treatment of unresectable MPM.MethodsA Markov model was developed to compare the cost and quality-adjusted life-year (QALY) of nivolumab plus ipilimumab and chemotherapy over a 10-year time horizon. Clinical efficacy and safety data were extracted from the CheckMate 743 trials. Health state utilities were obtained from published literature. Costs were collected from an US payer perspective. One-way and probabilistic sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness's results.ResultsIn the base case analysis, the incremental healthcare costs and QALYs for Nivolumab plus Ipilimumab vs. chemotherapy are $196,604.22 and 0.53, respectively, resulting an incremental cost-effectiveness ratio (ICER) of $372,414.28/QALYs for the model cohort of patients with locally advanced or metastatic MPM. However, Probabilistic sensitivity analysis showed that there was no probability that Nivolumab plus ipilimumab was cost-effective within the fluctuation range of other model parameters in first-line in unresectable MPM. The results of one-way sensitivity analysis showed that the cost of Nivolumab was the most sensitive parameter.ConclusionsThe ICER of Nivolumab plus ipilimumab is above the theoretical willingness-to-pay threshold in the U.S, which suggests that first-line nivolumab plus ipilimumab for unresectable MPM may be not a cost-effective choice.

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Advances in Immunotherapy of Malignant Pleural Mesothelioma

Cited by 8 publications

References 46 publications

Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma

Three distinct mechanisms underlying human γδ T cell-mediated cytotoxicity against malignant pleural mesothelioma

Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors

Cost-effectiveness of nivolumab plus ipilimumab as first-line treatment for American patients with unresectable malignant pleural mesothelioma

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