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• W4308376190 abstract "<h3>Background</h3> Despite significant success in treating hematological malignancies, adoptive cell therapies have yielded limited efficacy in solid tumors.¹ Macrophages are myeloid cells of the innate immune system and are naturally recruited to solid tumors,² where they have the potential to phagocytose tumor cells, activate the tumor microenvironment (TME), and prime a broad anti-tumor adaptive immune response via T cell recruitment and activation. We have previously developed chimeric antigen receptor macrophages (CAR-M) targeting HER2 and showed efficacy in a variety of pre-clinical models,³ with a Phase I clinical trial ongoing. Mesothelin is overexpressed in a variety of solid tumors, including mesothelioma, lung, pancreatic, and ovarian cancers.⁴ Here, we present preclinical data summarizing the development of CT-1119, a mesothelin targeted CAR-M for solid tumors. <h3>Methods</h3> Using the chimeric adenoviral vector Ad5f35, we engineered primary human macrophages to express a CAR comprising a human scFv targeted against human mesothelin. To assess the activity of CT-1119, <i>in vitro</i> cell based assays and <i>in vivo</i> murine xenograft models were utilized. Donor-matched untransduced (UTD) macrophages served as controls. <h3>Results</h3> Primary human CAR-M engineered with an Ad5f35 vector demonstrated high CAR expression, high viability, upregulated M1 (anti-tumor) macrophage markers, and downregulated M2 (pro-tumor) macrophage markers. CT-1119 demonstrated increased resistance to repolarization by M2 (pro-tumor) polarizing cytokines as compared to donor matched UTD macrophages. CT-1119 specifically bound mesothelin and binding was not impacted by mesothelin shedding. CT-1119 specifically phagocytosed multiple mesothelin expressing tumor cell lines in a CAR-dependent and antigen-dependent manner. CT-1119 demonstrated robust <i>in vitro</i> killing of the relevant tumor cell lines A549 and MES-OV expressing mesothelin. CAR engagement also induced the release of pro-inflammatory cytokines such as TNFα following stimulation with mesothelin in both cell-free and cell-based contexts in a dose-dependent manner. <i>In vivo</i>, CT-1119 significantly reduced tumor burden in a murine xenograft model of lung cancer. Similarly, human monocytes targeting mesothelin were successfully generated using the same Ad5f35 vector and demonstrated specific activity against mesothelin positive tumor cells. <h3>Conclusions</h3> The presented results demonstrate that CT-1119, an autologous human anti-mesothelin CAR-M, can cause phagocytosis, tumor cell killing, and pro-inflammatory cytokine release in response to stimulation with mesothelin. These results show that CAR-M is a feasible approach for the treatment of mesothelin expressing sold tumors via the potential for induction of a systemic anti-tumor response. <h3>References</h3> Hou A, Chen L, Chen Y, Navigating CAR-T cells through the solid-tumour microenvironment, <i>Nat Rev Drug Discov</i>. 2021; <b>20</b>:531–550. Biswas S, Allavena P, Mantovani A, Tumor associated macrophages: functional diversity, clinical significance, and open questions, <i>Semin Immunopathol</i>. 2013; <b>35</b>:585–600. Klichinsky M, et al, Human chimeric antigen receptor macrophages for cancer immunotherapy, <i>Nat Biotechnol</i>. 2020: 1–7. Lv J, Li P, Mesothelin as a biomarker for targeted therapy, <i>Biomarker Res</i>. 2019; <b>7</b>: 1–18. <h3>Ethics Approval</h3> All studies involving animals were approved by the IACUC of the Wistar Institute (protocol 201364)." @default.
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• W4308376190 date "2022-11-01" @default.
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• W4308376190 title "194 Pre-clinical development of CT-1119, a mesothelin targeting chimeric antigen receptor macrophage (CAR-M), for solid tumor immunotherapy" @default.
• W4308376190 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0194" @default.
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