Clinical Cancer Research

Our medical research library holds 50 studies published in Clinical Cancer Research (2007–2026). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 49 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: American Association for Cancer Research
• Published: 1995 to the present, United States
• Language: English
• ISSN: 1078-0432 (print), 1557-3265 (electronic)
• Its record in the NLM Catalog

2020s

• Irreversible Electroporation Enhances Solid Tumor Infiltration and Selective Cancer Cell Lysis by CAR T Cells. W.R. Vista, V. Malik, M.C. Sheehan, et al. 2026;32(13):2708-2721. PubMed · Publisher · Free full text

  Abstract

  Purpose: One recurring challenge in cell therapy for solid tumors is poor tumor infiltration of adoptively transferred T cells. We previously showed that a subablative dose of tumor-targeted radiation generates a chemokine gradient that promotes infiltration, proliferation, and a memory phenotype of chimeric antigen receptor (CAR) T cells in solid tumors. However, radiation is cytotoxic to infiltrating CAR T cells, limiting its repeated use.

  Experimental Design: We hypothesized that irreversible electroporation could generate a chemokine gradient that promotes CAR T-cell infiltration into solid tumors and that selective irreversible electroporation (sIRE) tuned for selective cancer cell lysis (thus sparing infiltrating CAR T cells) can be used in a repeated fashion. Using experimental screening and simulation models, we optimized sIRE parameters to kill cancer cells while sparing T cells.

  Results: Using 3D tumor mimics and mouse models of malignant pleural mesothelioma, we confirmed the therapeutic benefit of repeated sIRE. Chemokine secretion by cancer cells injured by sIRE promoted migration and tumor infiltration of systemically administered CAR T cells and facilitated sustained immunity in a tumor-rechallenge model.

  Conclusions: By leveraging a dual-purpose translational strategy-through direct cancer cell-targeted cytotoxicity and augmented CAR T-cell infiltration-sIRE can reduce cancer burden while preserving and enhancing CAR T-cell function.

  ©2026 American Association for Cancer Research.

• Ad-SGE-DKK3 Gene Therapy Overcomes Resistance to Immune Checkpoint Blockade in Pleural Mesothelioma. H.J. Jang, M. Patel, D.Y. Wang, et al. 2025;31(13):2639-2654. PubMed · Publisher · Free full text

  Abstract

  Purpose: Immune checkpoint inhibitors (ICI) have limited efficacy in pleural mesothelioma. We investigated the role of Dickkopf WNT signaling pathway inhibitor 3 (DKK3) in overcoming treatment resistance.

  Patients And Methods: We performed preclinical studies to elucidate DKK3's role in ICI-resistant mouse mesothelioma. Based on these findings, we conducted a single-arm, phase II clinical trial of a combination of Ad-SGE-DKK3 and nivolumab for chemotherapy-refractory epithelioid pleural mesothelioma, with the objective response rate as the primary outcome.

  Results: DKK3 was significantly reduced in human epithelioid mesothelioma. Overexpression of DKK3 in cancer cells activated the p53 pathway, enhanced glycolysis, increased surface PD-L1, and reduced extracellular vesicle secretion and the colony-stimulating factor 1. DKK3 sensitized the tumor immune microenvironment to ICIs and enabled the eradication of tumors by PD-1 blockade. In our trial, 12 patients received intratumoral Ad-SGE-DKK3 plus intravenous nivolumab. The objective response rate was 16.6%, and 41.7% had stable disease, for a 58.3% rate of durable clinical response. The median overall survival was 14.5 months, and the median progression-free survival was 4.5 months. Grade 3 adverse events occurred in 41.7% of patients. Serial tumor biopsies and serum analyses revealed that patients with durable clinical response had increased tumor-infiltrating bulk and effector memory CD8 T cells, reduced circulating memory CD8 T cells, and sustained lower soluble mesothelin and the colony-stimulating factor 1 levels compared with progressors.

  Conclusions: Combination Ad-SGE-DKK3 plus nivolumab demonstrated a tolerable safety profile and potential efficacy in patients with chemotherapy-refractory epithelioid pleural mesothelioma.

  ©2025 American Association for Cancer Research.

• Diffuse Pleural Mesotheliomas with Genomic Near-Haploidization: A Newly Recognized Subset with Distinct Clinical, Histologic, and Molecular Features. S.R. Yang, G. Jayakumaran, J. Benhamida, et al. 2024;30(13):2780-2789. PubMed · Publisher · Free full text

  Abstract

  Purpose: Diffuse pleural mesotheliomas (DPM) with genomic near-haploidization (GNH) represent a novel subtype first recognized by The Cancer Genome Atlas project; however, its clinicopathologic and molecular features remain poorly defined.

  Experimental Design: We analyzed clinical genomic profiling data from 290 patients with DPM using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. Allele-specific copy number analysis was performed using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm.

  Results: A total of 210 patients were evaluable for loss of heterozygosity (LOH) analysis using FACETS from MSK-IMPACT tumor:normal sequencing data. In this cohort, GNH, defined as LOH across >80% of the genome, was detected in 10 cases (4.8%). Compared with non-GNH tumors, GNH DPMs were associated with younger age and less frequent self-reported history of occupational asbestos exposure. Histologically, GNH DPMs were enriched in biphasic subtype (80% vs. 14.5%) and showed abundant tumor-infiltrating lymphocytes (TILs). Genomic analysis revealed a higher frequency of TP53 alterations, whereas SETDB1 mutations were present in nearly all and only in this subset. The clinicopathologic and molecular findings were further validated in a separate cohort. Despite the younger age, patients with GNH DPMs had a shorter overall survival (10.9 vs. 25.4 months, P = 0.004); the poor prognostic impact of GNH remained significant after controlling for biphasic histology. Of three patients with GNH DPMs who received immune checkpoint blockade, two achieved a clinician-assessed partial response.

  Conclusions: GNH defines an aggressive subtype of mainly biphasic DPMs in younger patients with recurrent alterations in SETDB1 and TP53. The enrichment in biphasic histology and TILs, together with our preliminary immune checkpoint blockade response data and anecdotal clinical trial data, suggests that further evaluation of immunotherapy may be warranted in this subset.

  ©2024 American Association for Cancer Research.

• Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Nonsmokers and Tobacco Smokers. B. Dalal, T. Tada, D.P. Patel, et al. 2024;30(16):3592-3602. PubMed · Publisher · Free full text

  Abstract

  Purpose: Nonsmokers account for 10% to 13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose CT (LDCT).

  Experimental Design: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified using liquid chromatography-mass spectrometry to determine if nonsmoker cases can be distinguished from sex and age-matched controls in comparison with tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening.

  Results: Urinary levels of CR and NANA were significantly higher and comparable in nonsmokers and tobacco smoker cases than population controls in both cohorts. Receiver operating characteristic analysis for combined CR and NANA levels in nonsmokers of the exploratory cohort resulted in better predictive performance with the AUC of 0.94, whereas the validation cohort nonsmokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in nonsmokers as well as tobacco smoker cases in both cohorts.

  Conclusions: Measuring CR and NANA in urine liquid biopsies could identify nonsmokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.

  ©2024 The Authors; Published by the American Association for Cancer Research.

• A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma. H.S. Lee, H.J. Jang, M. Ramineni, et al. 2023;29(3):548-559. PubMed · Publisher · Free full text

  Abstract

  Purpose: We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551).

  Patients And Methods: The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses.

  Results: Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells.

  Conclusions: These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.

  ©2022 American Association for Cancer Research.

• A (Controlled) Spill of IL2 for Localized Treatment of Mesothelioma. R. Palanki, K.L. Swingle, M.J. Mitchell. 2022;28(23):5010-5012. Editorial · Comment PubMed · Publisher · Free full text

  Abstract

  A microencapsulated, cell-based IL2 cytokine factory was recently developed, and the safety and efficacy of this platform in a mouse model of mesothelioma were demonstrated. This platform has the potential to overcome current challenges in the delivery of therapeutic cytokines for cancer immunotherapy. See related article by Nash et al., p. 5121.

  ©2022 American Association for Cancer Research.

• Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors. A.M. Nash, S. Aghlara-Fotovat, B. Castillio, et al. 2022;28(23):5121-5135. Editorial PubMed · Publisher · Free full text

  Abstract

  Purpose: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure.

  Experimental Design: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis.

  Results: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti-programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69-CD44+CD62L- T cells, reduction of CD86-PD-L1- M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.

  Conclusions: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010.

  ©2022 The Authors; Published by the American Association for Cancer Research.

• FDA Approval Summary: Nivolumab in Combination with Ipilimumab for the Treatment of Unresectable Malignant Pleural Mesothelioma. E.C. Nakajima, P.J. Vellanki, E. Larkins, et al. 2022;28(3):446-451. PubMed · Publisher · Free full text

  Abstract

  On October 2, 2020, FDA approved nivolumab with ipilimumab as first-line treatment for adult patients with unresectable malignant pleural mesothelioma (MPM). The approval was based on results from Study CA209743 (CHECKMATE-743), an open-label trial of patients with MPM randomized to receive nivolumab and ipilimumab for up to 2 years (n = 303) or six cycles of chemotherapy with cisplatin or carboplatin plus pemetrexed (n = 302). Overall survival (OS) was improved for patients who received nivolumab and ipilimumab, with a median OS of 18.1 months [95% confidence interval (CI), 16.8-21.5] compared with 14.1 months (95% CI: 12.5-16.2; HR, 0.74; 95% CI, 0.61-0.89; P = 0.002), for patients who received chemotherapy. The magnitude of benefit was larger for patients with non-epithelioid versus epithelioid histology. Additional clinical pharmacology data support an alternative dosing regimen of nivolumab than evaluated in the trial, which will reduce the number of required treatment visits. This application was reviewed under FDA's Project Orbis, in collaboration with Australia's Therapeutic Goods Administration, Switzerland's Swissmedic, Health Canada, and Brazil's National Health Surveillance Agency or ANVISA (Agência Nacional de Vigilância Sanitária). Nivolumab and ipilimumab is the first drug regimen approved by FDA for MPM since 2004.

  ©2021 American Association for Cancer Research.

• Somatic Epigenetic Silencing of RIPK3 Inactivates Necroptosis and Contributes to Chemoresistance in Malignant Mesothelioma. Y. Tan, E. Sementino, M. Cheung, et al. 2021;27(4):1200-1213. PubMed · Publisher · Free full text

  Abstract

  Purpose: Receptor-interacting protein kinase 3 (RIPK3) phosphorylates effector molecule MLKL to trigger necroptosis. Although RIPK3 loss is seen in several human cancers, its role in malignant mesothelioma is unknown. This study aimed to determine whether RIPK3 functions as a potential tumor suppressor to limit development of malignant mesothelioma.

  Experimental Design: RIPK3 expression was examined in 66 malignant mesothelioma tumors and cell lines. Promoter methylation and DNMT1 siRNA studies were performed to assess the mode of RIPK3 silencing in RIPK3-deficient malignant mesothelioma cells. Restoration of RIPK3 expression in RIPK3-negative malignant mesothelioma cells, either by treatment with 5-aza-2'-deoxycytidine or lentiviral expression of cDNA, was performed to assess effects on cell viability, necrosis, and chemosensitization.

  Results: Loss of RIPK3 expression was observed in 42/66 (63%) primary malignant mesotheliomas and malignant mesothelioma cell lines, and RT-PCR analysis demonstrated that downregulation occurs at the transcriptional level, consistent with epigenetic silencing. RIPK3-negative malignant mesothelioma cells treated with 5-aza-2'-deoxycytidine resulted in reexpression of RIPK3 and chemosensitization. Ectopic expression of RIPK3 also resulted in chemosensitization and led to necroptosis, the latter demonstrated by phosphorylation of downstream target MLKL and confirmed by rescue experiments. Mining of RIPK3 expression and survival outcomes among patients with malignant mesothelioma available from The Cancer Genome Atlas repository revealed that promoter methylation of RIPK3 is associated with reduced RIPK3 expression and poor prognosis.

  Conclusions: These data suggest that RIPK3 acts as a tumor suppressor in malignant mesothelioma by triggering necroptosis and that epigenetic silencing of RIPK3 by DNA methylation impairs necroptosis and contributes to chemoresistance and poor survival in this incurable disease.

  ©2020 American Association for Cancer Research.

• Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment. R. Chen, W.C. Lee, J. Fujimoto, et al. 2020;26(20):5477-5486. PubMed · Publisher · Free full text

  Abstract

  Purpose: Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied.

  Experimental Design: We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib.

  Results: The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib-treated tumors had significantly longer survival.

  Conclusions: Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.

  ©2020 American Association for Cancer Research.

• Expression of Concern: HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients. A. Napolitano, D.J. Antoine, L. Pellegrini, et al. 2020;26(6):1529. PubMed · Publisher

• Pediatric PK/PD Phase I Trial of Pexidartinib in Relapsed and Refractory Leukemias and Solid Tumors Including Neurofibromatosis Type I-Related Plexiform Neurofibromas. L.H. Boal, J. Glod, M. Spencer, et al. 2020;26(23):6112-6121. PubMed · Publisher · Free full text

  Abstract

  Purpose: Simultaneously targeting the tumor and tumor microenvironment may hold promise in treating children with refractory solid tumors. Pexidartinib, an oral inhibitor of tyrosine kinases including colony stimulating factor 1 receptor (CSF-1R), KIT, and FLT3, is FDA approved in adults with tenosynovial giant cell tumor. A phase I trial was conducted in pediatric and young adult patients with refractory leukemias or solid tumors including neurofibromatosis type 1-related plexiform neurofibromas.

  Patients And Methods: A rolling six design with dose levels (DL) of 400 mg/m2, 600 mg/m2, and 800 mg/m2 once daily for 28-day cycles (C) was used. Response was assessed at regular intervals. Pharmacokinetics and population pharmacokinetics were analyzed during C1.

  Results: Twelve patients (4 per DL, 9 evaluable) enrolled on the dose-escalation phase and 4 patients enrolled in the expansion cohort: median (lower, upper quartile) age 16 (14, 16.5) years. No dose-limiting toxicities were observed. Pharmacokinetics appeared linear over three DLs. Pharmacokinetic modeling and simulation determined a weight-based recommended phase II dose (RP2D). Two patients had stable disease and 1 patient with peritoneal mesothelioma (C49+) had a sustained partial response (67% RECIST reduction). Pharmacodynamic markers included a rise in plasma macrophage CSF (MCSF) levels and a decrease in absolute monocyte count.

  Conclusions: Pexidartinib in pediatric patients was well tolerated at all DL tested, achieved target inhibition, and resulted in a weight-based RPD2 dose.

  ©2020 American Association for Cancer Research.

2010s

• Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma. R. Hassan, E. Alley, H. Kindler, et al. 2019;25(19):5787-5798. PubMed · Publisher · Free full text

  Abstract

  Purpose: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with poor prognosis. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express mesothelin, a tumor-associated antigen highly expressed in MPM. CRS-207 induces antitumor immune responses and increases susceptibility of neoplastic cells to immune-mediated killing.

  Patients And Methods: Patients with unresectable MPM, ECOG 0 or 1, and adequate organ and pulmonary function were enrolled in this multicenter, open-label phase Ib study. They received two priming infusions of 1 × 109 CFU CRS-207, followed by pemetrexed/cisplatin chemotherapy, and CRS-207 booster infusions. Primary objectives were safety and induction of immune response. Secondary/exploratory objectives included tumor response, progression-free survival (PFS), overall survival (OS), immune subset analysis, and gene-expression profiling of tumor.

  Results: Of 35 evaluable patients, 89% (31/35) had disease control with one complete response (3%), 19 partial responses (54%), and 10 stable disease (29%). The estimated median duration of response was 5.0 months (95% CI, 3.9-11.5). The median PFS and OS were 7.5 (95% CI, 7.0-9.9) and 14.7 (95% CI, 11.2-21.9) months, respectively. Tumor size reduction was observed post-CRS-207 infusion prior to chemotherapy in 11 of 35 (31%) patients. No unexpected treatment-related serious adverse events or deaths were observed. IHC analysis of pre- and post-CRS-207 treatment tumor biopsies revealed possible reinvigoration and proliferation of T cells, increased infiltration of dendritic and natural killer cells, increased CD8:Treg ratio, and a shift from immunosuppressive M2-like to proinflammatory M1-like macrophages following CRS-207 administration.

  Conclusions: Combination of CRS-207 and chemotherapy induced significant changes in the local tumor microenvironment and objective tumor responses in a majority of treated patients.

  ©2019 American Association for Cancer Research.

• Nivo-lution in Mesothelioma. A.S. Mansfield, M.G. Zauderer. 2019;25(18):5438-5440. Comment PubMed · Publisher · Free full text

  Abstract

  The MERIT study was a single-arm, phase II clinical trial of nivolumab for the second- or third-line treatment of patients with malignant pleural mesothelioma in Japan. MERIT confirmed that PD-1 inhibition has activity in mesothelioma and led to the regulatory approval of nivolumab for the treatment of mesothelioma in Japan.See related article by Okada et al., p. 5485.

  ©2019 American Association for Cancer Research.

• Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients. S. Khanna, S. Graef, F. Mussai, et al. 2018;24(12):2859-2872. PubMed · Publisher · Free full text

  Abstract

  Purpose: The cross-talk between tumor cells, myeloid cells, and T cells can play a critical role in tumor pathogenesis and response to immunotherapies. Although the etiology of mesothelioma is well understood, the impact of mesothelioma tumor cells on the surrounding immune microenvironment is less well studied. In this study, the effect of the mesothelioma tumor microenvironment on circulating and infiltrating granulocytes and T cells is investigated.Experimental Design: Tumor tissues and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T-cell suppression potential. Different cocultures of granulocytes and/or mesothelioma tumor cells and/or T cells were set up to identify the mechanism of T-cell inhibition.Results: Analysis of human tumors showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T-cell proliferation and activation. Characterization of the whole blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared with healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of reactive oxygen species (ROS) from granulocytes, resulting in T-cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumors express GM-CSF and that higher GM-CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralizing antibody, or ROS inhibition, restored T-cell proliferation, suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients.Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma tumors and the immune microenvironment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy in patients with mesothelioma. Clin Cancer Res; 24(12); 2859-72. ©2018 AACR.

  ©2018 American Association for Cancer Research.

• A Randomized Phase II Trial of Adjuvant Galinpepimut-S, WT-1 Analogue Peptide Vaccine, After Multimodality Therapy for Patients with Malignant Pleural Mesothelioma. M.G. Zauderer, A.S. Tsao, T. Dao, et al. 2017;23(24):7483-7489. Randomized trial PubMed · Publisher · Free full text

  Abstract

  Purpose: Determine the 1-year progression-free survival (PFS) rate among patients with malignant pleural mesothelioma (MPM) receiving the WT1 peptide vaccine galinpepimut-S after multimodality therapy versus those receiving control adjuvants.Experimental Design: This double-blind, controlled, two center phase II trial randomized MPM patients after surgery and another treatment modality to galinpepimut-S with GM-CSF and Montanide or GM-CSF and Montanide alone. An improvement in 1-year PFS from 50% to 70% was the predefined efficacy threshold, and 78 patients total were planned. The study was not powered for comparison between the two arms.Results: Forty-one patients were randomized. Treatment-related adverse events were mild, self-limited, and not clinically significant. On the basis of a stringent prespecified futility analysis (futility = ≥10 of 20 patients on one arm experiencing progression < 1 year), the control arm closed early. The treatment arm was subsequently closed because of the resultant unblinding. The PFS rate at 1 year from beginning study treatment was 33% and 45% in the control and vaccine arms, respectively. Median PFS was 7.4 months versus 10.1 months and median OS was 18.3 months versus 22.8 months in the control and vaccine arms, respectively.Conclusions: The favorable safety profile was confirmed. PFS and OS were greater in those who received vaccine, but the trial was neither designed nor powered for comparison between the arms. On the basis of these promising results, the investigators are planning a larger randomized trial with greater statistical power to define the optimal use and benefit of galinpepimut-S in the treatment of MPM. Clin Cancer Res; 23(24); 7483-9. ©2017 AACR.

  ©2017 American Association for Cancer Research.

• Efficacy of Anti-mesothelin Immunotoxin RG7787 plus Nab-Paclitaxel against Mesothelioma Patient-Derived Xenografts and Mesothelin as a Biomarker of Tumor Response. J. Zhang, S. Khanna, Q. Jiang, et al. 2017;23(6):1564-1574. PubMed · Publisher · Free full text

  Abstract

  Purpose: The purpose of this study was to evaluate the antitumor efficacy of the reduced immunogenicity anti-mesothelin immunotoxin RG7787 plus nab-paclitaxel against primary mesothelioma cell lines and tumor xenografts and the utility of mesothelin as a biomarker of tumor response.Experimental Design: Early-passage human malignant mesothelioma cell lines NCI-Meso16, NCI-Meso19, NCI-Meso21, and NCI-Meso29 were evaluated for sensitivity to RG7787 or nab-paclitaxel alone or in combination. In addition, the antitumor activity of RG7787 plus nab-paclitaxel was evaluated using NCI-Meso16, NCI-Meso21, and NCI-Meso29 tumor xenografts in immunodeficient mice. Serum mesothelin was measured at different time points to determine whether its levels correlated with tumor response.Results: All four primary mesothelioma cell lines highly expressed mesothelin with 41 × 103 to 346 × 103 mesothelin sites per cell and were sensitive to RG7787, with IC50 ranging from 0.3 to 10 ng/mL. Except for NCI-Meso19, these cells were also sensitive to nab-paclitaxel, with IC50 of 10 to 25 ng/mL. In vitro, RG7787 plus nab-paclitaxel led to decreased cell viability compared with either agent alone. In NCI-Meso16 tumor xenografts, treatment with RG7787 plus nab-paclitaxel led to sustained complete tumor regressions. Similar antitumor efficacy was observed against NCI-Meso21 and NCI-Meso29 tumor xenografts. In all three tumor xenograft models, changes in human serum mesothelin correlated with response to therapy and were undetectable in mice with complete tumor regression with RG7787 and nab-paclitaxel.Conclusions: RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cells in vitro as well as in vivo, with serum mesothelin levels correlating with tumor response. These results indicate that this combination could be useful for treating patients with mesothelioma. Clin Cancer Res; 23(6); 1564-74. ©2016 AACR.

  ©2016 American Association for Cancer Research.

• HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients. A. Napolitano, D.J. Antoine, L. Pellegrini, et al. 2016;22(12):3087-96. PubMed · Publisher · Free full text

  Abstract

  Purpose: To determine whether serum levels of high mobility group box protein 1 (HMGB1) could differentiate malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls.

  Experimental Design: Hyperacetylated and nonacetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from malignant mesothelioma patients (n = 22), individuals with verified chronic asbestos exposure (n = 20), patients with benign pleural effusions (n = 13) or malignant pleural effusions not due to malignant mesothelioma (n = 25), and healthy controls (n = 20). Blood levels of previously proposed malignant mesothelioma biomarkers fibulin-3, mesothelin, and osteopontin were also measured in nonhealthy individuals.

  Results: HMGB1 serum levels reliably distinguished malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in malignant mesothelioma patients and asbestos-exposed individuals compared with healthy controls. Hyperacetylated HMGB1 was significantly higher in malignant mesothelioma patients compared with asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/mL, the sensitivity and specificity of serum hyperacetylated HMGB1 in differentiating malignant mesothelioma patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating malignant mesothelioma patients from patients with cytologically benign or malignant non-mesothelioma pleural effusion.

  Conclusions: Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyperacetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon. Clin Cancer Res; 22(12); 3087-96. ©2016 AACR.

  ©2016 American Association for Cancer Research.

• Mithramycin Depletes Specificity Protein 1 and Activates p53 to Mediate Senescence and Apoptosis of Malignant Pleural Mesothelioma Cells. M. Rao, S.M. Atay, V. Shukla, et al. 2016;22(5):1197-210. PubMed · Publisher · Free full text

  Abstract

  Purpose: Specificity protein 1 (SP1) is an oncogenic transcription factor overexpressed in various human malignancies. This study sought to examine SP1 expression in malignant pleural mesotheliomas (MPM) and ascertain the potential efficacy of targeting SP1 in these neoplasms.

  Experimental Design: qRT-PCR, immunoblotting, and immunohistochemical techniques were used to evaluate SP1 expression in cultured MPM cells and MPM specimens and normal mesothelial cells/pleura. MTS, chemotaxis, soft agar, β-galactosidase, and Apo-BrdUrd techniques were used to assess proliferation, migration, clonogenicity, senescence, and apoptosis in MPM cells following SP1 knockdown, p53 overexpression, or mithramycin treatment. Murine subcutaneous and intraperitoneal xenograft models were used to examine effects of mithramycin on MPM growth in vivo. Microarray, qRT-PCR, immunoblotting, and chromatin immunoprecipitation techniques were used to examine gene expression profiles mediated by mithramycin and combined SP1 knockdown/p53 overexpression and correlate these changes with SP1 and p53 levels within target gene promoters.

  Results: MPM cells and tumors exhibited higher SP1 mRNA and protein levels relative to control cells/tissues. SP1 knockdown significantly inhibited proliferation, migration, and clonogenicity of MPM cells. Mithramycin depleted SP1 and activated p53, dramatically inhibiting proliferation and clonogenicity of MPM cells. Intraperitoneal mithramycin significantly inhibited growth of subcutaneous MPM xenografts and completely eradicated mesothelioma carcinomatosis in 75% of mice. Mithramycin modulated genes mediating oncogene signaling, cell-cycle regulation, senescence, and apoptosis in vitro and in vivo. The growth-inhibitory effects of mithramycin in MPM cells were recapitulated by combined SP1 knockdown/p53 overexpression.

  Conclusions: These findings provide preclinical rationale for phase II evaluation of mithramycin in patients with mesothelioma.

  ©2015 American Association for Cancer Research.

• New Life for Immunotoxin Cancer Therapy. R. Hassan, C. Alewine, I. Pastan. 2016;22(5):1055-8. PubMed · Publisher · Free full text

  Abstract

  Immunotoxins are targeted anticancer therapeutics that kill cancer cells using a cytotoxic bacterial toxin payload. Their development for use in solid tumor malignancies was delayed due to issues with their immunogenicity and limited therapeutic window. However, new research has rejuvenated the field. Coadministration with a lymphocyte-depleting regimen of pentostatin and cyclophosphamide can delay antidrug antibody formation, increasing the number of treatment cycles that patients can receive and resulting in durable responses in heavily pretreated patients. In addition, a new generation of immunotoxin molecules with reduced immunogenicity and nonspecific toxicity has been developed through protein engineering techniques, and one has recently entered the clinic. In preclinical studies in mouse models, these new agents are effective against many tumor types as single agents, and also produce synergistic antitumor responses in combination with chemotherapy. These new immunotoxins have renewed excitement in the field and may prove a promising addition to the targeted therapy repertoire.

  ©2015 American Association for Cancer Research.

• Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. S.O. Dolly, A.J. Wagner, J.C. Bendell, et al. 2016;22(12):2874-84. PubMed · Publisher · Free full text

  Abstract

  Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases.

  Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed.

  Results: Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas).

  Conclusions: Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874-84. ©2016 AACR.

  ©2016 American Association for Cancer Research.

• Pilot and Feasibility Trial Evaluating Immuno-Gene Therapy of Malignant Mesothelioma Using Intrapleural Delivery of Adenovirus-IFNα Combined with Chemotherapy. D.H. Sterman, E. Alley, J.P. Stevenson, et al. 2016;22(15):3791-800. PubMed · Publisher · Free full text

  Abstract

  Purpose: "In situ vaccination" using immunogene therapy has the ability to induce polyclonal antitumor responses directed by the patient's immune system.

  Experimental Design: Patients with unresectable malignant pleural mesothelioma (MPM) received two intrapleural doses of a replication-defective adenoviral vector containing the human IFNα2b gene (Ad.IFN) concomitant with a 14-day course of celecoxib followed by chemotherapy. Primary outcomes were safety, toxicity, and objective response rate; secondary outcomes included progression-free and overall survival. Biocorrelates on blood and tumor were measured.

  Results: Forty subjects were treated: 18 received first-line pemetrexed-based chemotherapy, 22 received second-line chemotherapy with pemetrexed (n = 7) or gemcitabine (n = 15). Treatment was generally well tolerated. The overall response rate was 25%, and the disease control rate was 88%. Median overall survival (MOS) for all patients with epithelial histology was 21 months versus 7 months for patients with nonepithelial histology. MOS in the first-line cohort was 12.5 months, whereas MOS for the second-line cohort was 21.5 months, with 32% of patients alive at 2 years. No biologic parameters were found to correlate with response, including numbers of activated blood T cells or NK cells, regulatory T cells in blood, peak levels of IFNα in blood or pleural fluid, induction of antitumor antibodies, nor an immune-gene signature in pretreatment biopsies.

  Conclusions: The combination of intrapleural Ad.IFN, celecoxib, and chemotherapy proved safe in patients with MPM. OS rate was significantly higher than historical controls in the second-line group. Results of this study support proceeding with a multicenter randomized clinical trial of chemo-immunogene therapy versus standard chemotherapy alone. Clin Cancer Res; 22(15); 3791-800. ©2016 AACR.

  ©2016 American Association for Cancer Research.

• Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. R. Hassan, H.L. Kindler, T. Jahan, et al. 2014;20(23):5927-36. PubMed · Publisher · Free full text

  Abstract

  Purpose: Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its synergy with chemotherapy in preclinical studies, we evaluated the antitumor activity of amatuximab plus pemetrexed and cisplatin in patients with unresectable MPM.

  Experimental Design: In a single-arm phase II study, amatuximab (5 mg/kg) was administered on days 1 and 8 with pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on day 1 of 21-day cycles for up to six cycles. Patients with response or stable disease received amatuximab maintenance until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), response rate, and safety.

  Results: Eighty-nine patients were enrolled at 26 centers. Median of five cycles (range, 1-6) of combination treatment was administered, and 56 (63%) patients received amatuximab maintenance. Combination therapy resulted in no overlapping toxicities. Eleven patients (12.4%) had amatuximab-related hypersensitivity reactions. Responses included partial responses in 33 (40%) and stable disease in 42 (51%). Six-month PFS rate was 51% [95% confidence interval (CI), 39.1-62.3)], median PFS was 6.1 months (95% CI, 5.8-6.4), and median OS was 14.8 months (95% CI, 12.4-18.5) with 29 patients alive at data cut-off.

  Conclusions: Amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Although PFS was not significantly different from historical controls, the median OS was 14.8 months with a third of patients alive and 5 continuing to receive amatuximab at the time of analysis.

  ©2014 American Association for Cancer Research.

• T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo. C. Geldres, B. Savoldo, V. Hoyos, et al. 2014;20(4):962-71. PubMed · Publisher · Free full text

  Abstract

  Purpose: Because of its high expression on various types of tumors and its restricted distribution in normal tissues, chondroitin sulfate proteoglycan-4 (CSPG4) represents an attractive target for the antibody-based therapy of several solid tumors. We tested whether T cells transduced with a CSPG4-specific chimeric antigen receptor (CAR) inhibited the growth of CSPG4-expressing tumor cells both in vitro and in vivo.

  Experimental Design: We first independently validated by immunohistochemistry (IHC) the expression of CSPG4 in an extensive panel of tumor arrays and normal tissues as well as queried public gene expression profiling datasets of human tumors. We constructed a second-generation CSPG4-specific CAR also encoding the CD28 costimulatory endodomain (CAR.CSPG4). We then evaluated human T lymphocytes expressing this CAR for their ex vivo and in vivo antitumor activity against a broad panel of solid tumors.

  Results: IHC showed that CSPG4 is highly expressed in melanoma, breast cancer, head and neck squamous cell carcinoma (HNSCC), and mesothelioma. In addition, in silico analysis of microarray expression data identified other important potential tumors expressing this target, including glioblastoma, clear cell renal carcinoma, and sarcomas. T lymphocytes genetically modified with a CSPG4-CAR controlled tumor growth in vitro and in vivo in NSG mice engrafted with human melanoma, HNSCC, and breast carcinoma cell lines.

  Conclusions: CAR.CSPG4-redirected T cells should provide an effective treatment modality for a variety of solid tumors.

  ©2013 AACR

• Therapeutic efficacy of an Fc-enhanced TCR-like antibody to the intracellular WT1 oncoprotein. N. Veomett, T. Dao, H. Liu, et al. 2014;20(15):4036-46. PubMed · Publisher · Free full text

  Abstract

  Purpose: RMFPNAPYL (RMF), a Wilms' tumor gene 1 (WT1)-derived CD8 T-cell epitope presented by HLA-A*02:01, is a validated target for T-cell-based immunotherapy. We previously reported ESK1, a high avidity (Kd < 0.2 nmol/L), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1(+) and HLA-A*02:01(+) leukemia and solid tumor cell lines.

  Experimental Design: We engineered a second-generation mAb, ESKM, to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESKM was compared with native ESK1 in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. ESKM toxicity was assessed in HLA-A*02:01(+) transgenic mice.

  Results: ESK antibodies mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 μg/mL, but ESKM was about 5- to 10-fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 days vs. 6.5 days), but an identical biodistribution pattern in C57BL/6J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01(+) transgenic mice compared with the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage.

  Conclusions: The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein.

  ©2014 American Association for Cancer Research.

• Extracellular signal-regulated kinase 5: a potential therapeutic target for malignant mesotheliomas. A. Shukla, J.M. Miller, C. Cason, et al. 2013;19(8):2071-83. PubMed · Publisher · Free full text

  Abstract

  Purpose: Malignant mesothelioma is a devastating disease with a need for new treatment strategies. In the present study, we showed the importance of extracellular signal-regulated kinase 5 (ERK5) in malignant mesothelioma tumor growth and treatment.

  Experimental Design: ERK5 as a target for malignant mesothelioma therapy was verified using mesothelial and mesothelioma cell lines as well as by xenograft severe combined immunodeficient (SCID) mouse models.

  Results: We first showed that crocidolite asbestos activated ERK5 in LP9 cells and mesothelioma cell lines exhibit constitutive activation of ERK5. Addition of doxorubicin resulted in further activation of ERK5 in malignant mesothelioma cells. ERK5 silencing increased doxorubicin-induced cell death and doxorubicin retention in malignant mesothelioma cells. In addition, shERK5 malignant mesothelioma lines exhibited both attenuated colony formation on soft agar and invasion of malignant mesothelioma cells in vitro that could be related to modulation of gene expression linked to cell proliferation, apoptosis, migration/invasion, and drug resistance as shown by microarray analysis. Most importantly, injection of shERK5 malignant mesothelioma cell lines into SCID mice showed significant reduction in tumor growth using both subcutaneous and intraperitoneal models. Assessment of selected human cytokine profiles in peritoneal lavage fluid from intraperitoneal shERK5 and control tumor-bearing mice showed that ERK5 was critical in regulation of various proinflammatory (RANTES/CCL5, MCP-1) and angiogenesis-related (interleukin-8, VEGF) cytokines. Finally, use of doxorubicin and cisplatin in combination with ERK5 inhibition showed further reduction in tumor weight and volume in the intraperitoneal model of tumor growth.

  Conclusion: ERK5 inhibition in combination with chemotherapeutic drugs is a beneficial strategy for combination therapy in patients with malignant mesothelioma.

• Sequential binary gene ratio tests define a novel molecular diagnostic strategy for malignant pleural mesothelioma. A. De Rienzo, W.G. Richards, B.Y. Yeap, et al. 2013;19(9):2493-502. PubMed · Publisher · Free full text

  Abstract

  Purpose: To develop a standardized approach for molecular diagnostics, we used the gene expression ratio bioinformatic technique to design a molecular signature to diagnose malignant pleural mesothelioma (MPM) from among other potentially confounding diagnoses and differentiate the epithelioid from the sarcomatoid histologic subtype of MPM. In addition, we searched for pathways relevant in MPM in comparison with other related cancers to identify unique molecular features in MPM.

  Experimental Design: We conducted microarray analysis on 113 specimens including MPMs and a spectrum of tumors and benign tissues comprising the differential diagnosis of MPM. We generated a sequential combination of binary gene expression ratio tests able to discriminate MPM from other thoracic malignancies. We compared this method with other bioinformatic tools and validated this signature in an independent set of 170 samples. Functional enrichment analysis was conducted to identify differentially expressed probes.

  Results: A sequential combination of gene expression ratio tests was the best molecular approach to distinguish MPM from all the other samples. Bioinformatic and molecular validations showed that the sequential gene ratio tests were able to identify the MPM samples with high sensitivity and specificity. In addition, the gene ratio technique was able to differentiate the epithelioid from the sarcomatoid type of MPM. Novel genes and pathways specifically activated in MPM were identified.

  Conclusions: New clinically relevant molecular tests have been generated using a small number of genes to accurately distinguish MPMs from other thoracic samples, supporting our hypothesis that the gene expression ratio approach could be a useful tool in the differential diagnosis of cancers.

  ©2013 AACR.

• Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial. A.M. Gonzalez-Angulo, F. Meric-Bernstam, S. Chawla, et al. 2013;19(19):5474-84. PubMed · Publisher · Free full text

  Abstract

  Purpose: This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies.

  Experimental Design: nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m(2). Additional doses were 56.25, 100, 150, and 125 mg/m(2).

  Results: Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m(2) [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m(2) (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m(2). Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration-time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m(2), except for a relatively low AUC at 125 mg/m(2). nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1.

  Conclusions: The clinical dose of single-agent nab-rapamycin was established at 100 mg/m(2) weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies.

  ©2013 AACR.

• A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. D.T. Le, D.G. Brockstedt, R. Nir-Paz, et al. 2012;18(3):858-68. PubMed · Publisher · Free full text

  Abstract

  Purpose: Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses and activation and recruitment of natural killer (NK) and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T-cell responses against mesothelin-expressing murine tumors. These two phase I studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively.

  Experimental Design: A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1 × 10(6), 3 × 10(7), or 3 × 10(8) colony-forming units (cfu). CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic, or ovarian cancers. Seventeen subjects received up to 4 doses of 1 × 10(8), 3 × 10(8), 1 × 10(9), or 1 × 10(10) cfu.

  Results: A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1 × 10(9) cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, listeriolysin O and mesothelin-specific T-cell responses were detected and 37% of subjects lived ≥15 months.

  Conclusions: ANZ-100 and CRS-207 administration was safe and resulted in immune activation.

• CSPG4 as a target of antibody-based immunotherapy for malignant mesothelioma. Z. Rivera, S. Ferrone, X. Wang, et al. 2012;18(19):5352-63. PubMed · Publisher · Free full text

  Abstract

  Purpose: Malignant mesothelioma (MM) is an aggressive cancer, resistant to current therapies. Membrane chondroitin sulphate proteoglycan 4 (CSPG4), which has been successfully targeted in melanoma and breast cancer, was found highly expressed in MM, but not in normal mesothelium. Therefore, we explored CSPG4 as a suitable target for monoclonal antibody (mAb)-based immunotherapy for MM.

  Experimental Design: We assayed adhesion, motility, invasiveness, wound-healing, apoptosis, and anchorage-independent growth of MM cells on cell cultures. CSPG4 expression and signaling was studied by immunoblotting. The growth of MM severe combined immunodeficient (SCID) mice xenografts induced by PPM-Mill cells, engineered to express the luciferase reporter gene, was monitored by imaging, upon treatment with CSPG4 mAb TP41.2. Animal toxicity and survival were assayed in both tumor inhibition and therapeutic experiments.

  Results: CSPG4 was expressed on 6 out of 8 MM cell lines and in 25 out of 41 MM biopsies, with minimal expression in surrounding healthy cells. MM cell adhesion was mediated by CSPG4-dependent engagement of ECM. Cell adhesion was inhibited by mAb TP41.2 resulting in decreased phosphorylation of focal adhesion kinase (FAK) and AKT, reduced expression of cyclin D1 and apoptosis. Moreover, mAb TP41.2 significantly reduced MM cell motility, migration, and invasiveness, and inhibited MM growth in soft agar. In vivo, treatment with mAb TP41.2 prevented or inhibited the growth of MM xenografts in SCID mice, with a significant increase in animal survival.

  Conclusion: These results establish the safety of CSPG4 mAb-based immunotherapy and suggest that CSPG4 mAb-based immunotherapy may represent a novel approach for the treatment of MM.

• Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. E.L. Servais, C. Colovos, L. Rodriguez, et al. 2012;18(9):2478-89. PubMed · Publisher · Free full text

  Abstract

  Purpose: Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biologic function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases.

  Experimental Design: Human and murine MPM cells with MSLN forced expression and short hairpin RNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples.

  Results: MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, colocalized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n = 139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n = 72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors.

  Conclusions: Our data provide evidence elucidating a biologic role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN expressing MPM. As regional invasion is the characteristic feature in MSLN expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target.

  ©2012 AACR.

• Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. M. Carbone, H. Yang. 2012;18(3):598-604. PubMed · Publisher · Free full text

  Abstract

  Malignant mesothelioma is an aggressive malignancy related to asbestos and erionite exposure. AP-1 transcriptional activity and the NF-κB signaling pathway have been linked to mesothelial cell transformation and tumor progression. HGF and c-Met are highly expressed in mesotheliomas. Phosphoinositide 3-kinase, AKT, and the downstream mTOR are involved in cell growth and survival, and they are often found to be activated in mesothelioma. p16(INK4a) and p14(ARF) are frequently inactivated in human mesothelioma, and ∼50% of mesotheliomas contain the NF2 mutation. Molecular therapies aimed at interfering with these pathways have not improved the dismal prognosis of mesothelioma, except possibly for a small subset of patients who benefit from certain therapies. Recent studies have shown the importance of asbestos-induced inflammation in the initiation and growth of mesothelioma, and HMGB1 and Nalp3 inflammasome have been identified as key initiators of this process. Asbestos induces cell necrosis, causing the release of HMGB1, which in turn may activate Nalp3 inflammasome, a process that is enhanced by asbestos-induced production of reactive oxygen species. HMGB1 and Nalp3 induce proinflammatory responses and lead to interleukin-1β and TNF-α secretion and NF-κB activity, thereby promoting cell survival and tumor growth. Novel strategies that interfere with asbestos- and erionite-mediated inflammation might prevent or delay the onset of mesothelioma in high-risk cohorts, including genetically predisposed individuals, and/or inhibit tumor growth. The very recent discovery that germline BAP1 mutations cause a new cancer syndrome characterized by mesothelioma, uveal melanoma, and melanocytic tumors provides researchers with a novel target for prevention and early detection.

• New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. M. Ladanyi, M.G. Zauderer, L.M. Krug, et al. 2012;18(17):4485-90. PubMed · Publisher · Free full text

  Abstract

  Malignant pleural mesothelioma (MPM) is a highly lethal cancer with limited therapeutic options. Recent work has focused on the frequent somatic inactivation of two tumor suppressor genes in MPM-NF2 (Neurofibromatosis type 2) and the recently identified BAP1 (BRCA associated protein 1). In addition, germline mutations in BAP1 have been identified that define a new familial cancer syndrome, which includes MPM, ocular melanoma, and other cancers. These recent advances may allow screening of high-risk individuals and the development of new therapies that target key pathways in MPM.

  ©2012 AACR.

• Polycomb repressor complex-2 is a novel target for mesothelioma therapy. C.D. Kemp, M. Rao, S. Xi, et al. 2012;18(1):77-90. PubMed · Publisher · Free full text

  Abstract

  Purpose: Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. This study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM).

  Experimental Design: Microarray, quantitative reverse transcriptase PCR (qRT-PCR), immunoblot, and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral short hairpin RNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity, and tumorigenicity of MPM cells either exhibiting knockdown of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Microarray and qRT-PCR techniques were used to examine gene expression profiles mediated by knockdown of EZH2 or EED, or DZNep.

  Results: EZH2 and EED, which encode components of polycomb repressor complex-2 (PRC-2), were overexpressed in MPM lines relative to normal mesothelial cells. EZH2 was overexpressed in approximately 85% of MPMs compared with normal pleura, correlating with diminished patient survival. Overexpression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knockdown of EZH2 orEED, or DZNep treatment, decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knockdown of PRC-2 members or DZNep treatment.

  Conclusions: Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.

  © 2011 AACR.

• Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. E.K. Moon, C. Carpenito, J. Sun, et al. 2011;17(14):4719-30. PubMed · Publisher · Free full text

  Abstract

  Purpose: Adoptive T-cell immunotherapy with tumor infiltrating lymphocytes or genetically-modified T cells has yielded dramatic results in some cancers. However, T cells need to traffic properly into tumors to adequately exert therapeutic effects.

  Experimental Design: The chemokine CCL2 was highly secreted by malignant pleural mesotheliomas (MPM; a planned tumor target), but the corresponding chemokine receptor (CCR2) was minimally expressed on activated human T cells transduced with a chimeric antibody receptor (CAR) directed to the MPM tumor antigen mesothelin (mesoCAR T cells). The chemokine receptor CCR2b was thus transduced into mesoCAR T cells using a lentiviral vector, and the modified T cells were used to treat established mesothelin-expressing tumors.

  Results: CCR2b transduction led to CCL2-induced calcium flux and increased transmigration, as well as augmentation of in vitro T-cell killing ability. A single intravenous injection of 20 million mesoCAR + CCR2b T cells into immunodeficient mice bearing large, established tumors (without any adjunct therapy) resulted in a 12.5-fold increase in T-cell tumor infiltration by day 5 compared with mesoCAR T cells. This was associated with significantly increased antitumor activity.

  Conclusions: CAR T cells bearing a functional chemokine receptor can overcome the inadequate tumor localization that limits conventional CAR targeting strategies and can significantly improve antitumor efficacy in vivo.

• Fine-needle aspiration biopsies for gene expression ratio-based diagnostic and prognostic tests in malignant pleural mesothelioma. A. De Rienzo, L. Dong, B.Y. Yeap, et al. 2011;17(2):310-6. PubMed · Publisher · Free full text

  Abstract

  Purpose: Malignant pleural mesothelioma (MPM) is an aggressive disease associated with median survival between 9 and 12 months. The correct diagnosis of MPM is sometimes challenging and usually requires solid tissue biopsies rather than fine-needle aspiration biopsies (FNA). We postulated that the accuracy of FNA-based diagnosis might be improved by the addition of molecular tests using a gene expression ratio-based algorithm and that prognostic tests could be similarly performed.

  Experimental Design: Two MPM and 2 lung cancer cell lines were used to establish the minimal quantity of RNA required to perform the gene ratio test. On the basis of these results, 276 ex vivo FNA biopsies from 63 MPM patients and 250 ex vivo FNA samples from 92 lung cancer patients were analyzed using previously described diagnostic and prognostic tests based on gene expression ratios.

  Results: We found that the sensitivity of the diagnostic test for MPM was 100% [95% confidence interval (CI): 95%-100%] and the specificity in primary lung adenocarcinoma was 90% (95% CI: 81%-95%). The FNA-based prognostic classification was concordant among 76% (95% CI: 65%-87%) of patients with the risk assignment in a subset of the matched surgical specimens previously analyzed by the prognostic test.

  Conclusions: Sufficient RNA can be extracted from most FNA biopsies to perform gene expression molecular tests. In particular, we show that the gene expression ratio algorithms performed well when applied to diagnosis and prognosis in MPM. This study provides support for the development of additional RNA molecular tests that may enhance the utility of FNA in the management of other solid cancers.

  ©2010 AACR.

• Killing of resistant cancer cells with low Bak by a combination of an antimesothelin immunotoxin and a TRAIL Receptor 2 agonist antibody. X. Du, L. Xiang, C. Mackall, et al. 2011;17(18):5926-34. PubMed · Publisher · Free full text

  Abstract

  Purpose: Many solid tumors express cell surface mesothelin making them attractive targets for antibody-based therapies of cancer. SS1P [antimesothelin(Fv)PE38] is a recombinant immunotoxin (RIT) that has potent cytotoxic activity on several cancer cell lines and clinical activity in mesothelioma patients. Pancreatic cancers express mesothelin and are known to be resistant to most chemotherapeutic agents. The goal of this study is to treat pancreatic cancer with RIT by targeting mesothelin.

  Experimental Design: We measured the cytotoxic activity of an antimesothelin immunotoxin on pancreatic cancer cells. We also measured the levels of several pro- and antiapoptotic proteins, as well as the ability of TNF-related apoptosis-inducing ligand (TRAIL) or the anti-TRAIL receptor 2 agonist antibody (HGS-ETR2) to kill pancreatic cells, and the cytotoxic activity of the two agents together in cell culture and against tumors in mice.

  Results: In two pancreatic cancer cell lines, immunotoxin treatment inhibited protein synthesis but did not produce significant cell death. The resistant lines had low levels of the proapoptotic protein Bak. Increasing Bak expression enhanced the sensitivity to immunotoxins, whereas Bak knockdown diminished it. We also found that combining immunotoxin with TRAIL or HGS-ETR2 caused synergistic cell death, and together triggered caspase-8 recruitment and activation, Bid cleavage and Bax activation. Combining SS1P with HGS-ETR2 also acted synergistically to decrease tumor burden in a mouse model.

  Conclusion: Our data show that low Bak can cause cancer cells to be resistant to immunotoxin treatment and that combining immunotoxin with TRAIL or a TRAIL agonist antibody can overcome resistance.

  ©2011 AACR.

• Serum soluble mesothelin concentrations in malignant pleural mesothelioma: relationship to tumor volume, clinical stage and changes in tumor burden. J. Creaney, R.J. Francis, I.M. Dick, et al. 2011;17(5):1181-9. PubMed · Publisher

  Abstract

  Purpose: To examine the clinical utility of soluble mesothelin in patients with malignant pleural mesothelioma.

  Experimental Design: A total of 97 patients (female: 11; male: 86) were prospectively enrolled, longitudinal serum samples collected, and mesothelin concentrations determined. Baseline mesothelin levels were analyzed relative to tumor stage, presence of metastatic disease, the positron emission tomography (PET) parameters maximum standardized uptake value, tumor volume, total glycolytic volume, and survival. Changes in mesothelin level were correlated to objective response to chemotherapy, as assessed radiologically and by PET imaging, and with patient survival.

  Results: Baseline mesothelin levels greater than 5 nmol/L were a significant negative prognostic indicator (HR = 2.25; 95% CI, 1.20-4.21) and correlated with tumor stage and volume. In 55 patients who received chemotherapy, change in mesothelin correlated with radiological response (χ(2) = 11.32; P = 0.023) and change in metabolically active tumor volume (r = 0.58; P < 0.01). Median survival for patients with a reduction in mesothelin following chemotherapy (19 months) was significantly longer than for patients with increased mesothelin (5 months; P < 0.001).

  Conclusion: These findings show the potential value of changes in mesothelin levels for prognostication and monitoring of treatment response in mesothelioma.

  ©2010 AACR.

• High blood neutrophil-to-lymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. S.C. Kao, N. Pavlakis, R. Harvie, et al. 2010;16(23):5805-13. PubMed · Publisher

  Abstract

  Purpose: Asbestos-induced chronic inflammation is implicated in the pathogenesis of malignant mesothelioma (MM). We have investigated blood neutrophil-to-lymphocyte ratio (NLR), an index of systemic inflammation, as a prognostic factor in MM patients.

  Experimental Design: Patients with MM who had systemic therapy at participating institutes were studied. Potential prognostic factors such as age, gender, performance status, histologic subtype, and baseline laboratory parameters, including NLR, were analyzed. Overall survival from commencement of therapy was determined by the Kaplan-Meier method. Multivariate analyses using Cox Regression model were performed with significant factors (P ≤ 0.05) to determine their independent effect.

  Results: A total of 173 MM patients undergoing systemic therapy including 119 patients receiving first-line therapy and 54 patients receiving second- or third-line therapy were included in this retrospective evaluation. Forty-two percent of patients had an elevated NLR at baseline. The following variables were predictive of survival: female gender (P = 0.044), epithelioid histologic subtype (P < 0.001), baseline white blood cell count less than 8.3 × 10⁹/L (P = 0.008), baseline platelet count 400 × 10⁹/L or less (P = 0.05), and NLR of 5 or less (P < 0.001). After multivariate analysis, histologic epithelioid subtype [hazard ratio (HR) = 2.0; 95% confidence interval (CI) = 1.3-2.9; P = 0.001], and NLR less than 5 (HR = 2.7; 95% CI = 1.8-3.9; P < 0.001) remained independent predictors. The 1-year survival rate was 60% versus 26%, whereas the 2-year survival rate was 34% versus 10% for NLR less than 5 and 5 or greater, respectively. In the separate analyses of chemotherapy-naive and previously treated patient groups, NLR was an independent predictor of survival in both groups.

  Conclusion: Our results indicate that NLR is an independent predictor of survival for patients with MM undergoing systemic therapy.

  ©2010 AACR.

• Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. R. Hassan, S.J. Cohen, M. Phillips, et al. 2010;16(24):6132-8. PubMed · Publisher · Free full text

  Abstract

  Purpose: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a tumor differentiation antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD).

  Methods: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m(2). Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009.

  Results: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1-24 infusions). At the 400 mg/m(2) dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m(2) was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration.

  Conclusion: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m(2). In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.

  ©2010 AACR

2000s

• Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer. F.M. Johnston, M.C. Tan, B.R. Tan, et al. 2009;15(21):6511-8. PubMed · Publisher · Free full text

  Abstract

  Purpose: Mesothelin is a glycoprotein expressed on normal mesothelial cells and is overexpressed in several histologic types of tumors including pancreatic adenocarcinomas. A soluble form of mesothelin has been detected in patients with ovarian cancer and malignant mesothelioma, and has prognostic value. Mesothelin has also been considered as a target for immune-based therapies. We conducted a study on the potential clinical utility of mesothelin as a biomarker for pancreatic disease and therapeutic target pancreatic cancer.

  Experimental Design: Tumor cell-bound and soluble mesothelin in patients was evaluated by immunohistochemistry and ELISA, respectively. The in vitro cellular immune response to mesothelin was evaluated by INF gamma ELISA and intracellular cytokine staining for IFN gamma in CD4(+) and CD8(+) T cells. The level of circulating antibodies to mesothelin was measured by ELISA.

  Results: All tumor tissue from patients with pancreatic adenocarcinoma expressed mesothelin (n = 10). Circulating mesothelin protein was detected in patients with pancreatic adenocarcinoma (73 of 74 patients) and benign pancreatic disease (5 of 5) but not in healthy individuals. Mesothelin-specific CD4(+) and CD8(+) T cells were generated from peripheral blood lymphocytes of patients with pancreatic cancer in 50% of patients compared with only 20% of healthy individuals. Antibodies reactive to mesothelin were detected in <3% of either patients or healthy individuals.

  Conclusions: Circulating mesothelin is a useful biomarker for pancreatic disease. Furthermore, mesothelin-specific T cells can be induced in patients with pancreatic cancer. This suggests that mesothelin is a potential target for immune-based intervention strategies in pancreatic cancer.

• Imaging a Genetically Engineered Oncolytic Vaccinia Virus (GLV-1h99) Using a Human Norepinephrine Transporter Reporter Gene. P. Brader, K.J. Kelly, N. Chen, et al. 2009;15(11):3791-801. PubMed · Publisher · Free full text

  Abstract

  Purpose: Oncolytic viral therapy continues to be investigated for the treatment of cancer, and future studies in patients would benefit greatly from a noninvasive modality for assessing virus dissemination, targeting, and persistence. The purpose of this study was to determine if a genetically modified vaccinia virus, GLV-1h99, containing a human norepinephrine transporter (hNET) reporter gene, could be sequentially monitored by [(123)I]metaiodobenzylguanidine (MIBG) gamma-camera and [(124)I]MIBG positron emission tomography (PET) imaging.

  Experimental Design: GLV-1h99 was tested in human malignant mesothelioma and pancreatic cancer cell lines for cytotoxicity, expression of the hNET protein using immunoblot analysis, and [(123)I]MIBG uptake in cell culture assays. In vivo [(123)I]MIBG gamma-camera and serial [(124)I]MIBG PET imaging was done in MSTO-211H orthotopic pleural mesothelioma tumors.

  Results: GLV-1h99 successfully infected and provided dose-dependent levels of transgene hNET expression in human malignant mesothelioma and pancreatic cancer cells. The time course of [(123)I]MIBG accumulation showed a peak of radiotracer uptake at 48 hours after virus infection in vitro. In vivo hNET expression in MSTO-211H pleural tumors could be imaged by [(123)I]MIBG scintigraphy and [(124)I]MIBG PET 48 and 72 hours after GLV-1h99 virus administration. Histologic analysis confirmed the presence of GLV-1h99 in tumors.

  Conclusion: GLV-1h99 shows high mesothelioma tumor cell infectivity and cytotoxic efficacy. The feasibility of imaging virus-targeted tumor using the hNET reporter system with [(123)I]MIBG gamma-camera and [(124)I]MIBG PET was shown in an orthotopic pleural mesothelioma tumor model. The inclusion of human reporter genes into recombinant oncolytic viruses enhances the potential for translation to clinical monitoring of oncolytic viral therapy.

• Molecular alterations at 9q33.1 and polyploidy in asbestos-related lung cancer. P. Nymark, E. Kettunen, M. Aavikko, et al. 2009;15(2):468-75. PubMed · Publisher

  Abstract

  Purpose: Asbestos causes DNA damage and the fibers, together with tobacco smoke, have a synergistic effect on lung cancer risk. We recently identified 18 chromosomal regions that showed differences in DNA copy number between the lung tumors of asbestos-exposed and nonexposed patients. One of the previously identified asbestos-associated chromosomal regions at 9q was further analyzed for allelic imbalance and DNA copy number alterations (CNA) in the lung tumors of asbestos-exposed and nonexposed patients. In addition, the ploidy level of the tumors was studied.

  Experimental Design: Allelic imbalance was analyzed at 9q31.3-34.3 with 15 microsatellite markers in 52 lung tumor samples from asbestos-exposed and nonexposed patients. CNA at 9q32-34.3 were characterized by fluorescent in situ hybridization (FISH) with six bacterial artificial chromosome probes in 95 lung tumors. The ploidy level was analyzed in 100 lung tumors with FISH using three to five centromere probes.

  Results: Allelic imbalance at 9q31.3-q34.3 was found in all asbestos-exposed patient tumors (100%, 17 of 17) compared with 64% (14 of 22) in the nonexposed cases (P = 0.005). The most significant difference was detected at 9q33.1 (P = 0.002). FISH results showed that also CNA were more frequent at 9q33.1 in the three major histologic types of non-small-cell lung tumors of exposed patients, and the association showed a dose-dependent trend (P = 0.03). Furthermore, we detected more frequent polyploidy among the exposed (48%, 28 of 58) than among the nonexposed (29%, 12 of 42) patient tumors (P < 0.05).

  Conclusions: These results provide a basis for the development of a method to identify asbestos-related lung cancer on a molecular level.

• Osteopontin levels in an asbestos-exposed population. E.K. Park, P.S. Thomas, A.R. Johnson, et al. 2009;15(4):1362-6. PubMed · Publisher

  Abstract

  Purpose: Serum osteopontin levels in patients with malignant mesothelioma have been reported to be higher than in healthy subjects. This study assessed serum osteopontin levels in an asbestos-exposed population to test whether nonmalignant asbestos-related disorders could influence osteopontin levels.

  Experimental Design: This cross-sectional study evaluated serum osteopontin levels in 525 male subjects. Subjects were classified into six different diagnostic groups, including asbestosis (n=23), silicosis (n=20), diffuse pleural thickening (n=110), asbestosis and diffuse pleural thickening (n=13), pleural plaques (n=142), and healthy subjects with a history of asbestos exposure (n=217).

  Results: Mean serum osteopontin levels differed among the six groups (P<0.0001). Mean osteopontin values of the healthy individuals exposed to asbestos were significantly different from that of subjects with asbestosis (P<0.001) and diffuse pleural thickening (P<0.001). There was a significant difference in mean serum levels of osteopontin in healthy individuals exposed to asbestos (n=217) compared with the group mean of all subjects with asbestos-related disorders (n=288; P<0.0001).

  Conclusions: Our results suggest that osteopontin levels are elevated in subjects with asbestos-related disorders without malignant mesothelioma. These data indicate that osteopontin, although reported to be useful for detecting malignant mesothelioma in asbestos-exposed individuals, may be influenced by nonmalignant processes.

• Phase I trial of continuous infusion anti-mesothelin recombinant immunotoxin SS1P. R.J. Kreitman, R. Hassan, D.J. Fitzgerald, et al. 2009;15(16):5274-9. PubMed · Publisher · Free full text

  Abstract

  Purpose: To conduct a phase I trial of recombinant immunotoxin SS1P given by continuous infusion in chemoresistant solid tumors expressing mesothelin.

  Experimental Design: Eligible patients had mesothelioma, ovarian, or pancreatic cancer, which was recurrent or unresectable despite standard therapy, and were mesothelin positive by immunohistochemistry. SS1P was given by continuous infusion for 10 days, and cycles could be repeated at 4-week intervals in the absence of neutralizing antibodies or progressive disease.

  Results: Twenty-four patients, five with peritoneal mesothelioma, nine with pleural mesothelioma, two with pleural-peritoneal mesothelioma, seven with ovarian carcinoma, and one with pancreatic carcinoma, received 4, 8, 12, 18, and 25 microg/kg/d x10. The maximum tolerated dose was 25 microg/kg/d x10, where one of six patients had dose-limiting toxicity due to reversible vascular leak syndrome. Immunogenicity was observed in 18 (75%) of 24 patients, and five (21%) received a second cycle. Constant plasma levels of SS1P were maintained for most of the 10-day infusion time, with median peak levels of up to 153 ng/mL. One patient had a partial response. Nonmajor responses included cessation of ascites and independence from paracentesis, resolution of masses by positron emission tomography, and improved pain and range of motion.

  Conclusions: As a single agent by continuous infusion, recombinant immunotoxin SS1P was well tolerated up to 25 microg/kg/d x10 and showed evidence of modest clinical activity. Continuous infusion showed no significant advantage over bolus dosing, and further clinical development of SS1P is proceeding by bolus dosing in combination with chemotherapy.

• Protumorigenic role of HAPLN1 and its IgV domain in malignant pleural mesothelioma. A.V. Ivanova, C.M. Goparaju, S.V. Ivanov, et al. 2009;15(8):2602-11. PubMed · Publisher · Free full text

  Abstract

  Purpose: Tumor extracellular matrix (ECM) plays a crucial role in cancer progression mediating and transforming host-tumor interactions. Targeting the ECM is becoming an increasingly promising therapeutic approach in cancer treatment. We find that one of the ECM proteins, HAPLN1, is overexpressed in the majority of mesotheliomas. This study was designed to characterize the protumorigenic role of HAPLN1 in mesothelioma.

  Experimental Design: Overexpression of HAPLN1 was assessed and validated on a large set of normal/mesothelioma specimens on the RNA and protein levels. We also analyzed DNA copy number alterations in the HAPLN1 genomic locus using the array-based comparative genomic hybridization representational oligonucleotide microarray analysis tool. Tumorigenic activities of the HAPLN1 domains were evaluated in vitro on mesothelioma cells transfected with HAPLN1-expressing constructs.

  Results: We found that HAPLN1 is 23-fold overexpressed in stage I mesothelioma and confirmed it for 76% samples (n = 53) on RNA and 97% (n = 40) on protein levels. The majority of lung cancers showed no differential expression of HAPLN1. Analysis of DNA copy number alterations identified recurrent gain in the 5q14.3 HAPLN1 locus in approximately 27% of tumors. Noteworthy, high expression of HAPLN1 negatively correlated with time to progression (P = 0.05, log-rank test) and overall survival (P = 0.006). Proliferation, motility, invasion, and soft-agar colony formation assays on mesothelioma cells overexpressing full-length HAPLN1 or its functional domains strongly supported the protumorigenic role of HAPLN1 and its SP-IgV domain.

  Conclusion: Overexpression of HAPLN1 and its SP-IgV domain increases tumorigenic properties of mesothelioma. Thus, targeting the SP-IgV domain may be one of the therapeutic approaches in cancer treatment.

• Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma. K. Shiomi, Y. Hagiwara, K. Sonoue, et al. 2008;14(5):1431-7. PubMed · Publisher

  Abstract

  Background: Because mesothelioma initially progresses on the surface of the pleura and peritoneum without forming masses, it has been difficult to diagnose at an early stage. It would be very useful to identify a tumor marker that could be used for screening to enable more diagnoses to be made at an early, treatable stage.

  Materials And Methods: We had previously identified N-ERC/mesothelin as a potential biomarker for mesothelioma. In the current work, we used a newly developed ELISA system to gain data on N-ERC/mesothelin levels in various clinical settings. A total of 102 healthy volunteers were recruited. In addition, 39 patients were diagnosed with mesothelioma, 53 patients were diagnosed with diseases that should be distinguished from mesothelioma, and 201 subjects were diagnosed with asbestos-related nonmalignant diseases (including simple exposure to asbestosis) who were treated at any of the cooperating hospitals were enrolled.

  Results: Serum N-ERC/mesothelin levels measured by a new ELISA system showed that the median values from patients with mesothelioma were extremely high compared with levels obtained from other patients. Analysis in terms of histologic type showed that serum levels of N-ERC/mesothelin were elevated in epithelioid type mesothelioma, especially. In four important models of clinical settings, the sensitivity and specificity of N-ERC/mesothelin were about 71% to 90% and 88% to 93%, respectively.

  Conclusion: N-ERC/mesothelin is a very promising tumor marker for mesothelioma, especially epithelioid mesothelioma.

• Bortezomib inhibits nuclear factor-kappaB dependent survival and has potent in vivo activity in mesothelioma. A. Sartore-Bianchi, F. Gasparri, A. Galvani, et al. 2007;13(19):5942-51. PubMed · Publisher

  Abstract

  Purpose: Purpose of this study has been the assessment of nuclear factor-kappaB (NF-kappaB) as a survival factor in human mesothelial cells (HMC), transformed HMC and malignant mesothelioma (MMe) cells. We aimed at verifying whether the proteasome inhibitor Bortezomib could abrogate NF-kappaB activity in MMe cells, leading to tumor cell death and may be established as a novel treatment for this aggressive neoplasm.

  Experimental Design: In HMC and MMe cells, NF-kappaB nuclear translocation and DNA binding were studied by electrophoretic mobility shift assay, following treatment with tumor necrosis factor-alpha (TNF-alpha). The IKK inhibitor Bay11-7082 was also tested to evaluate its effects on HMC, transformed HMC, and MMe cell viability upon exposure to asbestos fibers. Following Bortezomib treatment, cytotoxicity of MMe cells was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, whereas apoptosis and cell-cycle blockade were investigated by high-content analysis. Bortezomib was also given to mice bearing i.p. xenografts of MMe cells, and its effects on tumor growth were evaluated.

  Results: Here, we show that NF-kappaB activity is a constitutive survival factor in transformed HMC, MMe cells, and acts as a survival factor in HMC exposed to asbestos fibers. Bortezomib inhibits NF-kappaB activity in MMe cells and induces cell cycle blockade and apoptosis in vitro as well as tumor growth inhibition in vivo.

  Conclusions: Inhibition of NF-kappaB constitutive activation in MMe cells by Bortezomib resulted in in vitro cytotoxicity along with apoptosis and in vivo tumor regression. Our results support the use of Bortezomib in the treatment of MMe and has led to a phase II clinical trial currently enrolling in Europe.

• Clinical significance of serum mesothelin in patients with mesothelioma and lung cancer. A. Cristaudo, R. Foddis, A. Vivaldi, et al. 2007;13(17):5076-81. PubMed · Publisher

  Abstract

  Purpose: High levels of serum-soluble mesothelin family proteins (SMRP) have been found to be associated with malignant mesothelioma (MM), but not lung cancer (LC). To verify the clinical role of this marker for both these tumors, we tested serum SMRP in the largest population of thoracic cancers ever assembled.

  Experimental Design: SMRP blood concentrations were measured in 107 patients with MM, 215 patients with LC, 130 patients with benign respiratory diseases (BRD), and 262 controls. Statistical comparison between mean serum SMRP levels in all groups was done and receiver operating characteristic curves were constructed to evaluate the performance of this marker.

  Results: SMRP levels were significantly higher in patients with MM and LC than in patients with benign respiratory diseases and controls (P < 0.001). The area under the receiver operating characteristic curve for serum SMRP discriminating MM and controls was 0.77 (95% confidence interval, 0.71-0.83), with a best cutoff of 1.00 nmol/L (sensitivity, 68.2%; specificity, 80.5%). In both MM and LC, serum SMRP levels did not differ significantly between early and late stages. High SMRP levels proved to be an independent negative prognostic factor in patients with MM.

  Conclusions: Our data confirm that serum SMRP is a promising marker for the diagnosis, prognosis, and clinical monitoring of MM. We found that serum SMRP dosage may prove helpful in LC diagnosis as well. These data may also have positive repercussions on secondary preventive medical strategies for workers previously exposed to asbestos.

• Utility of osteopontin and serum mesothelin in malignant pleural mesothelioma diagnosis and prognosis assessment. B.D. Grigoriu, A. Scherpereel, P. Devos, et al. 2007;13(10):2928-35. PubMed · Publisher

  Abstract

  Purpose: Malignant mesothelioma is a highly aggressive tumor and is often diagnosed too late for a curative treatment. We compared diagnostic and prognostic values of mesothelin and osteopontin in 172 patients suspected of malignant pleural mesothelioma (MPM) and in a control group of 112 asymptomatic asbestos-exposed subjects.

  Experimental Design: Osteopontin and mesothelin were assayed with commercial ELISA kits in a series of 43 patients with pleural metastases of various carcinomas, 33 patients with benign pleural lesions associated with asbestos exposure, 96 patients with MPMs, and 112 asbestos-exposed healthy subjects. Results were correlated with patient's diagnosis and survival.

  Results: Serum osteopontin level was higher in MPM patients compared with healthy asbestos-exposed subjects and had a good capability to distinguish between these two populations. However, osteopontin was unable to distinguish between MPM and pleural metastatic carcinoma or benign pleural lesions associated with asbestos exposure. Neither plasma nor pleural fluid osteopontin were more powerful in this respect. Serum mesothelin had a good ability for diagnosing MPM but was unable to identify patients with nonepithelioid mesothelioma subtypes. Survival analysis identified tumor histologic subtype along with serum osteopontin and serum mesothelin as independent prognostic factors in mesothelioma patients.

  Conclusions: Osteopontin has a lower diagnostic accuracy than mesothelin in patients suspected of MPM. Insufficient specificity limits osteopontin utility as diagnostic marker. Both molecules have a potential value as prognostic markers.

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