bims-mesote 2021-02-21 papers

Issue of 2021–02–21
three papers selected by
Laura Mannarino, Mario Negri Institute

Biomark Res. 2021 Feb 15. 9(1): 11

Anti-Mesothelin CAR T cell therapy for malignant mesothelioma.

Laura Castelletti, Dannel Yeo, Nico van Zandwijk, John E J Rasko.

Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

Keywords: CAR T cells; Cancer; Immunotherapy; Malignant mesothelioma; Malignant pleural mesothelioma; Mesothelin; Tumor microenvironment

DOI: https://doi.org/10.1186/s40364-021-00264-1

Thorac Cancer. 2021 Feb 19.

Mediastinal undifferentiated pleomorphic sarcoma with pleural effusion cytopathologically misdiagnosed as epithelial malignant pleural mesothelioma: An autopsy case report.

Kinnosuke Matsumoto, Yukihiro Nakamura, Yuji Inagaki, Yoshihiko Taniguchi, Akihiro Tamiya, Yoshinobu Matsuda, Takahiko Kasai, Shinji Atagi.

Undifferentiated pleomorphic sarcoma (UPS) is a new disease in the World Health Organization's classification of tumors of soft tissue and bone published in 2013. Primary mediastinal UPS is rare, especially with pleural effusion. Herein, we describe the pathological findings of pleural effusion followed by mediastinal UPS, which was initially misdiagnosed as epithelial malignant pleural mesothelioma (MPM). The cytopathological findings of the pleural effusion cell block often contribute to the diagnosis of various malignant tumors. However, these findings may lead to misdiagnosis of highly invasive mediastinal tumors such as UPS. A biopsy for primary mediastinal lesions should be performed because MPM rarely mimics mediastinal tumors with pleural effusion.

Keywords: cell block; malignant pleural mesothelioma; mediastinum; pleural effusion; undifferentiated pleomorphic sarcoma

DOI: https://doi.org/10.1111/1759-7714.13898

Clin Lung Cancer. 2021 Jan 07. pii: S1525-7304(21)00003-6. [Epub ahead of print]

Subtypes of EGFR- and HER2-Mutant Metastatic NSCLC Influence Response to Immune Checkpoint Inhibitors.

Sally C M Lau, Aline Fusco Fares, Lisa W Le, Kate M Mackay, Spencer Soberano, Sze Wah Chan, Elliot Smith, Malcolm Ryan, Ming Sound Tsao, Penelope A Bradbury, Prodipto Pal, Frances A Shepherd, Geoffrey Liu, Natasha B Leighl, Adrian G Sacher.

INTRODUCTION: The efficacy of immune checkpoint inhibitors (ICIs) is low among EGFR-mutated non-small-cell lung cancer (NSCLC), although prolonged responses have occasionally been reported. We investigated the association between mutation subtypes and ICI outcomes among HER2- and EGFR-mutated NSCLC.
PATIENTS AND METHODS: This retrospective single-center study analyzed patients with EGFR- and HER2-mutated advanced NSCLC who received at least 1 cycle of ICI between 2013 and 2019. Patient characteristics, mutation subtype, and ICI outcomes.
RESULTS: Among 48 patients with advanced NSCLC, 14 (29%) had HER2 mutations and 34 (71%) had EGFR mutations. EGFR mutations included 16 (47%) exon 19 deletion, 7 (21%) L858R, 5 (15%) uncommon, and 6 (18%) exon 20 insertion. Compared to EGFR-sensitizing mutations (ESMs), HER2 and EGFR exon 20 mutations were associated with a trend toward better response (respectively, ESM, HER2, and EGFR exon 20: 11%, 29%, and 50%; P = .07) and significantly better disease control rates (respectively, 18%, 57%, and 67%; P = .008). Compared to ESM, HER2 mutations (adjusted hazard ratio, 0.35; P = .02) and EGFR exon 20 mutations (adjusted hazard ratio, 0.37; P = .10 trend) were also associated with improved PFS. Programmed death ligand 1 (PD-L1) expression remained an independent predictor of PFS (adjusted hazard ratio, 0.42; 95% confidence interval, 0.23-0.76; P = .004). The 6-month PFS rates were 29% (HER2), 33% (EGFR exon 20), and 4% (ESM). ICIs were generally well tolerated in this population. Importantly, no immune-related toxicity was observed in 10 patients who received a tyrosine kinase inhibitor (TKI) as the immediate next line treatment after ICI.
CONCLUSION: HER2 and EGFR exon 20 mutations derive greater benefit from ICIs with comparable PFS to wild-type historical second/third-line unselected cohorts. ICIs remain a treatment option for this genomic subgroup, given the absence of approved targeted therapies for these rare mutations.

Keywords: Driver mutations; Immunotherapy; Oncogene addiction; PD-1 inhibitors; PD-L1

DOI: https://doi.org/10.1016/j.cllc.2020.12.015