Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial

Calabrò, Luana; Morra, Aldo; Fonsatti, Ester; Cutaia, Ornella; Amato, Giovanni; Giannarelli, Diana; Giacomo, Anna Maria Di; Danielli, Riccardo; Altomonte, Maresa; Mutti, Luciano; Maio, Michele

doi:10.1016/s1470-2045(13)70381-4

Cited by 317 publications

(220 citation statements)

References 31 publications

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“…In the second-line setting, 2 out of 29 patients with MPM (7%) demonstrated a durable partial response to tremelimumab 15 mg/kg every 90 days (MESOT-TREM-2008) (175). Retrospective exposure-response analysis of data from melanoma suggested the dosing schedule of tremelimumab 15 mg/kg every 90 days resulted in underexposure to tremelimumab.…”

Section: Ctla4 Inhibitionmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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Section: Ctla4 Inhibitionmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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“…4 Immune checkpoint blocking antibodies, such as anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have shown a durable antitumor immune effect for several types of cancer, [5][6][7] and are under clinical investigation for MPM. 8,9 High number of CD8 C tumorinfiltrating lymphocytes (TILs) was suggested as a good prognostic factor in MPM patients, 10 indicating that TILs could play a pivotal role in host antitumor response.…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma

et al. 2017

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To investigate the link between the genomic landscape of cancer cells and immune microenvironment in tumor tissues, we characterized somatic mutations and tumor-infiltrating lymphocytes (TILs) in malignant pleural mesothelioma (MPM), including mutation/neoantigen load, spatial heterogeneity of somatic mutations of cancer cells and TILs (T-cell receptor b (TCRb) repertoire), and expression profiles of immunerelated genes using specimens of three different tumor sites (anterior, posterior, and diaphragm) obtained from six MPM patients. Integrated analysis identified the distinct patterns of somatic mutations and the immune microenvironment signatures both intratumorally and interindividually. MPM cases showed intratumoral heterogeneity in somatic mutations with unique TCRb clonotypes of TILs that were restricted to each tumor site, suggesting the presence of a neoantigen-related immune response. Correlation analyses showed that higher neoantigen load was significantly correlated with stronger clonal expansion of TILs (p D 0.048) and a higher expression level of an immune-associated cytolytic factor (PRF1 (p D 0.0041) in tumor tissues), suggesting that high neoantigen loads in tumor cells might promote expansion of functional tumor-specific T cells in the tumor bed. Our results collectively indicate that MPM tumors constitute a diverse heterogeneity in both the genomic landscape and immune microenvironment, and that mutation/neoantigen load may affect the immune microenvironment in MPM tissues.

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“…2,17,18 Along this line, the increase of the absolute leukocyte cell count (ALC) or of circulating CD4 C T cells expressing the inducible co-stimulatory molecule (ICOS) have been documented in relation with anti-CTLA-4 mAb therapies. 12,[19][20][21] ICOS C T cells that were augmented by IPI therapy in tumor lesions from prostate cancer patients, represented lymphocytes endowed with antitumor activity. 22,23 Moreover, increased levels in the periphery of central memory or effector memory CD4 C and CD8 C T cells have been described in patients undergoing IPI treatment, although there was no correlation with the clinical outcome.…”

Section: Introductionmentioning

confidence: 99%

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

Maccalli

Giannarelli²,

Capocefalo³

et al. 2015

OncoImmunology

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Moreover, either the absence or the presence of soluble NKG2D ligands (ULBP-1 or ¡2) at baseline in the serum of MM patients enabled to discriminate subjects with long-term survival (median overall survival, (OS) D 33.6 mo for ULBP-1 and ¡2) from poor survivors (OS D 9.8 or 6.6 mo, respectively). Conversely, no significant association between the levels of soluble MICA, MICB and ULBP-3 and the clinical outcome of patients was observed. An inverse correlation between circulating levels of these molecules at baseline and frequency of either CD3 C CD4 C CD45RO C BTLA C or Th17 or CD3 C CD4 C 4-1BB C T cells occurred in patients with a favorable clinical outcome. The simultaneous monitoring of different immune parameters, though validation in a large cohort of patients is needed, allowed to identify an association between phenotypic and soluble markers representing a possible predictive immunological signature for the clinical activity of IPI plus FTM.

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Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial

Cited by 317 publications

References 31 publications

Novel systemic therapy against malignant pleural mesothelioma

Novel systemic therapy against malignant pleural mesothelioma

Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

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