Background: We have conducted a Phase 1 trial of gavo-cel, an autologous genetically engineered anti-mesothelin T cell receptor fusion construct (TRuC™) cell therapy in pts with refractory mesothelin-expressing mesothelioma (MPM), ovarian cancer (OvC), cholangiocarcinoma (CHO), or non-small cell lung cancer (NCT03907852). Methods: T cells were engineered with a lentiviral vector to express an anti-mesothelin single domain antibody fused to the CD3ε subunit, which upon translation, integrated into and reprogrammed native T cell receptors to target mesothelin-expressing cancer cells in an HLA-independent manner. Eligibility required central laboratory confirmation of 2+ or 3+ mesothelin expression by IHC in ≥50% of tumor cells. Dose escalation followed a modified 3+3 design. Results: At data cut-off date (January 17^th, 2023), 32 pts (23 MPM, 8 OvC, 1 CHO) received a gavo-cel infusion at one of 7 dose levels (DL): DL0 (n = 1, no lymphodepletion [LD]) and DL1 (n = 8), 5x10⁷ transduced cells/m²; DL2 (n = 1, no LD) and DL3 (n = 13), 1x10⁸ transduced cells/m²; DL3.5 (n = 5), 3x10⁸ transduced cells/m²; DL4 (n = 1, no LD) and DL5 (n = 3), 5x10⁸ transduced cells/m². Median number of prior therapies was 5 (range, 1-13), including immune checkpoint inhibitors (ICI) in 87% of MPM pts. Bridging therapy was required in 24 (75%) pts. Two DLTs were reported: grade (gr) 3 pneumonitis at DL1 and gr5 bronchoalveolar hemorrhage at DL5. At the RP2D (1x10⁸/m² after LD) 2/13 (15%) pts had reversible gr≥3 CRS. The ORR and disease control rate was 20% and 77%, respectively. The 6-month OS rate was 70.2%. The ORR of pts with MPM or OvC receiving gavo-cel after LD was 21% and 29%, respectively. The median PFS and OS in MPM was 5.6 and 11.1 mos and in OvC was 5.8 and 9.4 mos. Responses correlated with declines in soluble mesothelin related peptides. Peak expansion and persistence correlated with dose and LD administration. At the RP2D, the median C_max was 14,385 copies/ug gDNA (range, 64.4–100,782) and the median peripheral blood (PB) persistence was 84 days (range: 0-170). Consistent elevation in IL-6 and IFN-γ levels but minimal IL-8 and TNF-α were observed. Gavo-cel expanded preferentially in cancerous tissues, where it was detected long after becoming undetectable in PB. Gavo-cel therapy led to increased CD3⁺CD8⁺ T cell tumor infiltration. Non-responders exhibited upregulation of immunoinhibitory ligands (CD155, PDL1), indicating potential resistance mechanisms. Conclusions: A single IV gavo-cel infusion at the RP2D was associated with a manageable toxicity profile and high rates of disease control, including objective responses in pts with refractory MPM and OvC. A phase 2 study is underway testing the safety and efficacy of gavo-cel in combination with checkpoint inhibitors in pts with mesothelin-expressing solid tumors. Clinical trial information: NCT03907852.