Immune checkpoint inhibitors in malignant pleural mesothelioma: promises and challenges

Ceresoli, Giovanni Luca; Bonomi, Maria; Sauta, Maria Grazia

doi:10.1080/14737140.2016.1191951

Cited by 10 publications

(10 citation statements)

References 15 publications

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“…Monolayers of mesothelioma cell lines were incubated with 1x10 6 T-cells overnight, (effector:target ratio of 1:1). Cytokine measurements were performed by ELISA.…”

Section: Cytotoxicity and Cytokine Release Assaysmentioning

confidence: 99%

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Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

et al. 2017

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Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4 T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma.

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“…Monolayers of mesothelioma cell lines were incubated with 1x10 6 T-cells overnight, (effector:target ratio of 1:1). Cytokine measurements were performed by ELISA.…”

Section: Cytotoxicity and Cytokine Release Assaysmentioning

confidence: 99%

“…Promising data have emerged from clinical trials of immune checkpoint blockade in this disease [6]. In parallel, there has been increasing interest in the development of adoptive immunotherapeutic approaches using genetically engineered T-cells.…”

Section: Introductionmentioning

confidence: 99%

Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

et al. 2017

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“…A study by Patel and colleagues finding increased tumor expression of PD-L1 after treatment with VSV–IFNβ in a murine model of non-small-cell lung cancer indicates the potential of PD-1/PD-L1 agents to increase efficacy ( 65 ). Early phase trials with immune checkpoint inhibitors for mesothelioma are in process, with promising preliminary results ( 157 ).…”

Section: Oncolytic Viral Therapy For Mesotheliomamentioning

confidence: 99%

Oncolytic Viral Therapy for Mesothelioma

Pease

Kratzke

2017

Front. Oncol.

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The limited effectiveness of conventional therapy for malignant pleural mesothelioma demands innovative approaches to this difficult disease. Even with aggressive multimodality treatment of surgery, radiation, and/or chemotherapy, the median survival is only 1–2 years depending on stage and histology. Oncolytic viral therapy has emerged in the last several decades as a rapidly advancing field of immunotherapy studied in a wide spectrum of malignancies. Mesothelioma makes an ideal candidate for studying oncolysis given the frequently localized pattern of growth and pleural location providing access to direct intratumoral injection of virus. Therefore, despite being a relatively uncommon disease, the multitude of viral studies for mesothelioma can provide insight for applying such therapy to other malignancies. This article will begin with a review of the general principles of oncolytic therapy focusing on antitumor efficacy, tumor selectivity, and immune system activation. The second half of this review will detail results of preclinical models and human studies for oncolytic virotherapy in mesothelioma.

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“…An example of immune checkpoint inhibition is the strategy of targeting and blocking CTLA-4. CTLA-4 is a cell surface co-factor expressed on the surface of T cells that acts as an inhibitory cofactor for CD80 and CD86 [ 73 ]. CTLA-4 competes with CD28 for binding with CD80/86 and when bound sends an inhibitor signal to antigen presenting cells to decrease the inflammatory response and diminish cell activation.…”

Section: Current Therapiesmentioning

confidence: 99%

“…Binding PD-L1 with ligand specific mAbs therefore blocks this tumor escape mecha-nism, potentially resulting in greater susceptibility of MPM to immune destruction. In the recent KEYNOTE-028 phase I clinical trial, the PD-1 mAb pembrolizumab was tested in a 25 patient cohort and showed an impressive overall disease control rate of 76% [ 73 , 78 ]. This has prompted larger phase II investigation to further explore the anti-MPM activity of pembrolizumab [ 73 ].…”

Section: Current Therapiesmentioning

confidence: 99%

Current and Emerging Therapy for Malignant Pleural Mesothelioma: Focus on CD26/Dipeptidyl Peptidase IV as a Therapeutic Target

Doonan

Ohnuma

Dang

et al. 2017

CCTR

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Background: Malignant mesothelioma is a largely incurable disease that is refractory to current therapies. CD26 is a multifunctional cell surface protein involved in autoimmune disease, diabetes, and cancer. It has a role in T cell function, extracellu-lar protein modification, as a prognostic factor for cancer, and as a therapeutic target for malignant mesothelioma. New treatment strategies are urgently needed for malig-nant pleural mesothelioma (MPM), and CD26-targeted therapy represents a novel ap-proach.Outline: In this review, the most current and up-to-date literature available was reviewed and the current state of malignant mesothelioma treatment is described. Throughout the review the need for new therapeutic approaches is highlighted in the shortcomings of current therapy. CD26 is a target that is fit to take on these shortcom-ings. In this review we discuss the structure and function of CD26, its role in malignant mesothelioma and the future of anti-CD26 therapy as a versatile immunotherapeutic option.Conclusion: This review highlights the areas of most promise in treating MPM, these in-clude immune checkpoint blockade, passive immunization, and based on our recently published data, targeting of CD26 with its specific mAb. Finally we describe how the an-ti-CD26 mAb YS110 was recently evaluated in the first-in-human phase I clinical trial, showing prolonged disease stabilization and a favorable side effect profile. Through better understanding of CD26, new pathways to treating and potentially curing malig-nant mesothelioma may be discovered.

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Immune checkpoint inhibitors in malignant pleural mesothelioma: promises and challenges

Cited by 10 publications

References 15 publications

Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

Oncolytic Viral Therapy for Mesothelioma

Current and Emerging Therapy for Malignant Pleural Mesothelioma: Focus on CD26/Dipeptidyl Peptidase IV as a Therapeutic Target

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