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- W4308398756 abstract "<h3>Background</h3> Gavo-cel is an autologous and HLA-independent <b>T</b>-Cell <b>R</b>eceptor F<b>u</b>sion <b>C</b>onstruct (TRuC<sup>TM</sup>) T cell therapy that targets mesothelin-expressing tumors and is under Phase 2 evaluation for treatment-resistant MPM, NSCLC, cholangiocarcinoma, and ovarian cancer tumors (NCT03907852). Mesothelin (MSLN) is a 71 kDa GPI-anchored membrane protein that undergoes proteolytic membrane shedding to generate soluble mesothelin-related peptides (sMRPs) whose levels are correlated with tumor burden in MPM. sMRPs contain the juxtamembrane epitope of that is recognized by the MH1 binder domain of the gavo-cel TRuC and whose levels are correlated with tumor burden in MPM. Because shed MLSN has been implicated as a potential obstacle to successful anti-MSLN therapies, including cell therapies, we assessed the impact of soluble MSLN (sMSLN) on the function of gavo-cel and or allogeneic anti-MSLN TRuC, MH1gd. <h3>Methods</h3> In this study, we generated primary human TRuC-T cells modeling MSLN-targeting clinical agent gavo-cel or that express MH1gd TRuC, and then measured the impact of soluble MSLN on the <i>in vitro</i> activation, cytotoxicity, and cytokine response of gavo-cel or MH1gd during acute and chronic challenge with antigen-expressing tumor cells. We also evaluated whether sMRP in human serum impacts the <i>in vitro</i> cytotoxicity and cytokine response of gavo-cel in response to MSLN-expressing tumor cell lines. <h3>Results</h3> High, supraphysiological levels of the full-length shed domain of MSLN, sMSLN, does not impair, block, or disrupt the effector function of gavo-cel or MH1gd TRuC-T cells with respect to <i>in vitro</i> cytotoxicity or cytokine production. Furthermore, gavo-cel demonstrates potent efficacy <i>in vivo</i> in a tumor model characterized by circulating sMSLN. <h3>Conclusions</h3> Our data indicate that both gavo-cel and allogeneic MSLN-targeting TRuC-T cells are not susceptible to functional suppression by sMRPs, even at supraphysiological levels that far exceed those found in cancer patients." @default.
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- W4308398756 date "2022-11-01" @default.
- W4308398756 modified "2023-09-25" @default.
- W4308398756 title "219 The functional activity of gavo-cel TRuC-T cells is not impaired by soluble mesothelin" @default.
- W4308398756 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0219" @default.
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