Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors.
Significance:
Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.
See related commentary by Aldea et al., p. 2674.
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2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.
Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumours through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumours. Little is known as to how morphology reflects tumour evolutionary history and disease progression. Whole exome sequencing data generated from 805 primary tumour regions and 121 paired metastatic tumours across 248 LUADs from the TRACERx 421 cohort, as well as RNA-Seq data from 463 primary tumour regions, were integrated with detailed histopathological analysis of tumour morphology at the whole and regional tumour level. Tumours with predominantly high-grade architectural patterns showed increased chromosomal complexity, with higher levels of loss of heterozygosity (LOH) and subclonal somatic copy number alterations (SCNAs). Individual regions in predominantly high-grade pattern tumours tended to be highly proliferative and less clonally diverse, potentially reflective of large recent subclonal expansions. Co-occurence of truncal loss/LOH of chromosome 3p and 3q was enriched in predominantly low/mid-grade tumours, whilst purely undifferentiated solid pattern tumours had a higher frequency of truncal 3q gains and
SMARCA4
gene alterations compared with other subtypes, including mixed solid pattern tumours, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumours tend to evolve towards higher grade patterns. The presence of micropapillary pattern and ‘spread through air spaces’ (STAS) were associated with an increased risk of intra-thoracic-only recurrence, in contrast to the presence of solid/cribriform patterns, necrosis, and pre-operative circulating tumour DNA (ctDNA) detection, which were associated with increased risk of extra-thoracic recurrence. Overall, these data provide insights into the relationship between LUAD histological subtypes and their underlying evolutionary genomic landscape, as well as clinical risk and clonal nature of metastatic dissemination.
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