ImmunoPET can demonstrate the necessary delivery, binding, and internalization of an ADC antibody in vivo and this correlates with the efficacy of mesothelin-targeted ADC in tumors vulnerable to the cytotoxic drug delivered.
In this review we will focus on the discovery and clinical usages of mesothelin and provide an update on other mesothelioma biomarkers and show how such biomarker studies might impact on the management of this deadly tumor in the future.
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.<b>Conclusions:</b> RG7787 plus nab-paclitaxel is very active against primary human mesothelioma cells <i>in vitro</i> as well as <i>in vivo</i>, with serum mesothelin levels correlating with tumor response.
Comprehensive immunohistochemical study of mesothelin (MSLN) using different monoclonal antibodies 5B2 and MN-1 in 1562 tumors with evaluation of its prognostic value in malignant pleural mesothelioma.
Tumorigenic and metastatic effects of MSLN were examined by tumor sphere formation, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo.
This includes the tumor-associated antigen (TAA) mature mesothelin, a 40kDa cell surface-bound antigen that is overexpressed in several malignancies including lung ovarian and pancreatic cancer.
In this study, mice vaccinated with Meso-VAX and adeno-associated virus (AAV)-IL-12 exhibited dramatic increases in the number of mesothelin-specific CD4(+) helper and CD8(+) cytotoxic T-cell precursors, higher titers of anti-mesothelin Abs and in vitro tumor killing activity, and all of these mice were tumor-free after 60 days of tumor challenge.
Although it has been assumed that shed antigen is a barrier to immunotoxin action, a modeling study predicted that shed MSLN may enhance the action of MSLN-targeting recombinant immunotoxins such as SS1P and similar therapeutics by facilitating their redistribution within tumors.
Many preclinical and clinical studies that target tumors with high mesothelin expression with antibodies, immunotoxins, antibody-drug conjugates and vaccines have shown the potential of mesothelin as a target.
Reactivity of TILs against tumor-associated antigens (mesothelin, survivin, or NY-ESO-1) was detected by intracellular cytokine production by flow cytometry.
Finally, vaccination of mice with the Ad5-PK vector resulted in enhanced T-cell-mediated interferon gamma (IFN-γ) release in response to both mesothelin peptide and a tumor line expressing mesothelin.
This technique was used in a database comprising 19,746 tumors to identify for 41 tumor types the percentage of samples with an overexpression of MSLN compared to a normal background.
MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy.
Our results suggest that mesothelin is a prognostic breast tumor marker whose expression is highly enriched in triple negative breast cancer (TNBC) tumors.
Human T cells expressing CAR targeting mesothelin or fibroblast activation protein and containing CD3ζ and 4-1BB cytoplasmic domains were intravenously injected into immunodeficient mice bearing large, established human mesothelin-expressing flank tumors.
SS1P is a recombinant immunotoxin composed of an antimesothelin Fv fragment fused to a truncated portion of Pseudomonas exotoxin A. SS1P targets and kills mesothelin-expressing tumors, which include mesothlioma as well as ovarian, lung, and pancreatic cancers.
A recombinant immunotoxin against the tumor-associated antigen mesothelin reengineered for high activity, low off-target toxicity, and reduced antigenicity.