Immunotherapy for Malignant Mesothelioma and Lung Cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

1. Exploiting mesothelin for mesothelioma therapy and related translational research Our current studies are focused on using immunotherapy directed against the tumor differentiation antigen mesothelin, which is expressed on normal mesothelial cells lining the pleura, pericardium, and peritoneum, but is highly expressed in several human tumors especially mesothelioma, ovarian cancer, lung cancer and pancreatic adenocarcinomas. This differential expression of mesothelin makes it an attractive candidate for tumor specific therapy. Our efforts are now focused on exploiting it for mesothelioma therapy using different approaches. These include anti mesothelin immunotoxin (LMB-100), an anti-mesothelin drug conjugate (BAY 94-9343), mesothelin vaccine (CRS-207) and adoptive T-cell therapy (TC-210). We are currently developing mesothelin-targeting adoptive cellular therapy, using chimeric antigen receptor (CAR)-T cells. Majority of the anti-mesothelin antibodies in clinical development target the membrane distal region of mesothelin, that could partly account for the lack of activity of anti-mesothelin CAR-T cell therapy in the clinic. To improve CAR-T cell anti-tumor activity, we propose a new approach i.e. developing anti-mesothelin CAR-T cells that target an epitope close to the surface of tumor cells. My collaborator, Dr. Mitchell Ho, has identified a high affinity rabbit monoclonal antibody (YP218) specific for region III, which is located at the C-terminal end of mesothelin close to the tumor cell surface. We have tested the cytotoxicity of the hYP218 CAR-T construct on several mesothelin expressing cell lines and anti-tumor effect in animal models. The pre-clinical studies have shown increased tumor killing (1). This construct is now under clinical development. Parallelly, we are conducting a clinical trial of a T-cell receptor fusion construct (TRuCs). Unlike other constructs, TRuCs are naturally incorporated into the native TCR complex, thus exploiting the full potential of TCR-driven T cell activation, effector function, and regulation. LMB-100 is an immunotoxin consisting of the anti-mesothelin Fv linked to a truncated form of the potent bacterial toxin, Pseudomonas exotoxin A, which has been de-immunized to decrease its antigenicity. We have recently completed the phase I trial of LMB-100 and established its safety and maximum tolerated dose (MTD), published in Cancer (2). Currently, we are evaluating the results of a recently concluded a phase II study of LMB-100 in patients with mesothelioma, in combination with immune checkpoint inhibitor Pembrolizumab. Since LMB-100 causes systemic inflammation and increase in immune cell infiltration in patient tumors, we hypothesized that intra- tumoral injection of LMB-100 would lead to increased inflammation and immune cell infiltration. Administering checkpoint inhibitors would further increase tumor-cell killing. We are presently conducting a phase 1 clinical trial in patients with mesothelioma where they are intratumorally administered LMB-100 on days 1 and 4 followed by CTLA-4 checkpoint inhibitor, ipilimumab, given i.v. on day 2 of a 21 day cycle. Patients will receive 2 cycles of LMB-100 plus ipilimumab, followed by 2 cycles of ipilimumab alone. Tumor biopsies will be performed prior to each administration of LMB-100, to evaluate changes in the tumor immune microenvironment. The trial is recruiting patients. We have previously shown that germline mutations in DNA repair genes increases sensitivity to platinum therapy and improves overall survival in patients with pleural mesothelioma (3). Currently, my laboratory is studying germline mutations in DNA repair genes that could predispose to mesothelioma and influence clinical outcome. We are enrolling patients and their relatives harboring such mutations for a long term follow up study, for early cancer detection and prevention. In the laboratory, we have focused on developing in-vitro and in-vivo models of human mesothelioma. We have established several early passage tumor cell lines from ascites and pleural fluid of patients. We have evaluated the morphological and genetic characteristics of these cell lines and are using them to study in-vitro drug sensitivity. Additionally, we have established a humanized mesothelioma xenograft tumor model with patient derived tumor cells and human PBMCs from healthy donor for in-vivo studies. As the development of Graft Versus Host Disease (GVHD) in the PBMC-humanized mouse model limits assessment of duration of anti-tumor efficacy, we have developed a syngeneic immunocompetent mouse model. Because the immunotoxin LMB-100 can target human mesothelin specifically, we established a human mesothelin expressing immunocompetent syngeneic mouse tumor model by transfecting PD-L1 positive mouse lung adenocarcinoma cell line with a hMSLN expressing vector encoding the membrane bound fragment of hMSLN. These cell lines were used to develop tumor. We have studied the effect of LMB-100 in combination with anti-PD1 antibody in both the models and have seen tumor regression. We have published our findings in Science Translational Medicine (4). These models are essential to evaluate novel therapeutic agents for mesothelioma and for the mechanistic studies of anti-tumor efficacy. Other ongoing laboratory studies are focused on understanding the mesothelioma tumor immune micro-environment and changes following treatment with anti-mesothelin targeted agents. 2. Immunotherapy to treat lung cancers. We are currently conducting clinical trial of the anti-PD-L1 monoclonal antibody MSB0010718C in patients with lung adenocarcinoma who have failed prior therapies. Our laboratory has recently shown that about 25% of patients with metastatic lung adenocarcinoma highly express mesothelin. Mesothelin expression in these tumors is highly associated with KRAS mutations and wild type EGFR status and is, independently, associated with poor prognosis. Our hypothesis is that patients with K-RAS mutant lung cancer can benefit from mesothelin directed therapies. Clinical trials of mesothelin directed therapies for treating lung cancer are about to open. Our laboratory is also studying the role of immune checkpoints in malignant mesothelioma so that drugs targeting this pathway can be exploited for treating mesothelioma. We are currently conducting a Phase II trial of NSCLC patients treated with LMB-100 in combination with pembrolizumab.