Zucali PA, Perrino M, Lorenzi E, Ceresoli GL, De Vincenzo F, Simonelli M, Gianoncelli L, De Sanctis R, Giordano L, Santoro A, Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma

Zucali PA, Perrino M, Lorenzi E, Ceresoli GL, De Vincenzo F, Simonelli M, Gianoncelli L, De Sanctis R, Giordano L, Santoro A, Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma. received PD-1 inhibitor (pembrolizumab, 9; nivolumab, 1) after progression on LMB-100 was 40%, and the median overall survival was 11.9 months. Of the seven evaluable patients, four had objective tumor responses, including one complete response and three partial responses, and the overall survival for these patients was 39.0+, 27.7, 32.6+, and 13.8 months. When Asimadoline stratified with regard to programmed death ligand 1 (PD-L1) expression, four of five patients with tumor PD-L1 expression had objective Rabbit Polyclonal to MT-ND5 tumor response. Asimadoline Patients with positive tumor PD-L1 expression also had increased progression-free survival (11.3 versus 2.1 months, = 0.0018) compared with those lacking PD-L1 expression. There was no statistically significant difference in overall survival (27.7 versus 6.8 months, = 0.1). LMB-100 caused a systemic inflammatory response and recruitment of CD8+ T cells in patients tumors. The enhanced antitumor effects with LMB-100 plus Asimadoline antiCPD-1 antibody were also observed in a human peripheral blood mononuclear cellCengrafted mesothelioma mouse model and a human mesothelinCexpressing syngeneic lung adenocarcinoma mouse model. LMB-100 plus pembrolizumab is now being evaluated in a prospective clinical trial for patients with mesothelioma. INTRODUCTION Immune checkpoint inhibitors including cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1) blocking antibodies have shown antitumor activity in patients with cancer and are approved for many solid tumors, including advanced melanoma, nonCsmall cell lung cancer (NSCLC), renal cell carcinoma, and bladder cancer (1, 2). Despite this, a large proportion of patients do not respond to these therapies (3, 4) because of multiple factors, including insufficient infiltration of activated CD8+ T cells into the tumor (5). A major focus of many laboratory and clinical studies is to improve the effectiveness of immune checkpoint inhibitors by combining them with agents that could make tumors more Asimadoline sensitive to these therapies. Malignant mesothelioma is a rare cancer with poor prognosis, and patients have limited treatment options after frontline chemotherapy with pemetrexed and cisplatin (6). Although immune checkpoint inhibitors are not approved by the U.S. Food and Drug Administration (FDA) for treatment of mesothelioma, several clinical trials of these agents have demonstrated a response rate of 9 to 20% in this disease (7C9). Other clinical trials are evaluating mesothelin-targeted therapies in patients with mesothelioma (10). Mesothelin, a glycosylphosphatidylinositol-anchored membrane glycoprotein, is highly expressed in many malignancies, including mesothelioma, NSCLC, pancreatic cancer, and ovarian cancer (11, 12), while only present in a very restricted manner on normal adult tissues, such as the mesothelial lining of the pleura, peritoneum, and pericardium (13). This expression pattern makes mesothelin an attractive target antigen, resulting in clinical trials of a variety of therapeutics targeting mesothelin, including antibody-based therapies, vaccines, and chimeric antigen receptor (CAR) T cells (14, 15). LMB-100 is a next-generation recombinant immunotoxin consisting of a humanized anti-mesothelin Fab fused to a 24-kDa truncated exotoxin A (PE) fragment with mutations that suppress B and T cell epitopes to reduce the immunity against the immunotoxin (16, 17). PE is specifically delivered into mesothelin-positive cancer cells after binding to mesothelin. The toxin portion reaches the cytosol, where it ADP (adenosine diphosphate)Cribosylates elongation factor 2, arrests protein synthesis, and induces immunogenic cell death (18). This mechanism of cell killing differs from that of currently approved chemotherapies or targeted agents used to treat solid tumors (19). The antitumor effectiveness of LMB-100 has been demonstrated in several mesothelin-expressing tumor models, including mesothelioma patientCderived xenograft (PDX) models (20). A phase 1 medical trial has established the security of LMB-100 in individuals (ClinicalTrials.gov “type”:”clinical-trial”,”attrs”:”text”:”NCT02798536″,”term_id”:”NCT02798536″NCT02798536). During the medical trial of LMB-100, we mentioned that some individuals with mesothelioma treated with the immunotoxin who consequently received pembrolizumab experienced major and long-lasting tumor regressions. Here, we have explained these medical responses in detail and sought to understand their mechanistic basis by evaluating changes in individuals tumors after LMB-100 therapy. We also carried out preclinical studies to validate the medical observations. Because the human being mesothelin (hMSLN)Cexpressing syngeneic mouse tumor model we developed previously is sensitive to CTLA-4 blockade but not to PD-1/PD-L1 blockade (21, 22), we generated additional animal models to characterize the antitumor effectiveness of LMB-100 plus antiCPD-1 antibodies. RESULTS Characteristics of individuals who received pembrolizumab or nivolumab after LMB-100 treatment Twenty-one individuals with malignant mesothelioma were treated with LMB-100 in the National Tumor Institute (NCI) on a phase 1 study to determine the maximum tolerated dose (MTD) and security of LMB-100 as a single agent (= 10) or in combination with nab-paclitaxel (= 11) (ClinicalTrials.gov “type”:”clinical-trial”,”attrs”:”text”:”NCT02798536″,”term_id”:”NCT02798536″NCT02798536) Asimadoline from July 2016 to April 2018. Nine of these individuals consequently went on to receive immunotherapy off protocol with pembrolizumab, and one individual received nivolumab at the time of disease progression. Of these 10 individuals,.