Abstract CT104: Initial results of a first in human dose-escalation study of KIR-CAR in patients with advanced mesothelin-expressing solid tumors

Abstract SynKIR-110 is a novel mesothelin-targeting autologous chimeric antigen receptor (CAR) T cell modeled after multichain immune receptors derived from natural killer cells, used in a first in human (FIH) phase 1 clinical trial to treat patients with advanced mesothelin-expressing solid tumors. Mesothelin-targeting single-chain variable fragment SS1 was recombined with killer-immunoglobulin-like receptor (KIR), which interacts with DNAX-activation protein of 12 kDa (DAP12) to induce effector T cell function. Preclinical studies with KIR-CAR showed decreased PD1 and Tim3 T cell exhaustion markers, with increased in vivo antitumor activity and decreased cytokine secretion compared with conventional CAR T. In this study, we assessed the safety and activity of SynKIR-110 in patients. A phase 1 dose-escalation study in patients with advanced ovarian cancer, mesothelioma, or cholangiocarcinoma who were refractory to standard of care treatment was conducted at four medical centers in the United States. Patients in dose cohorts 1-3 received a single intravenous dose of 1, 3, or 10 × 107 transduced SynKIR-110 T cells/m2, respectively, following lymphodepletion (LD) with cyclophosphamide and fludarabine; follow-up was for 12 months or until disease progression. Primary endpoints included safety and determination of a maximum tolerated dose (MTD) for a dose-expansion to evaluate anti-tumor activity. Circulating biomarkers were used to measure SynKIR-110 persistence and T cell activation. Clinical responses were evaluated via computed-tomography imaging starting 28 days after treatment. This ongoing study is registered with ClinicalTrials.gov NCT05568680. In cohorts 1-3, no dose-limiting toxicities or events meeting protocol-defined stopping criteria were reported. Three of 9 (33%) patients treated experienced low-grade cytokine release syndrome (≤grade 2), with no immune effector cell-associated neurologic events (0/9). Five of 9 (56%) patients experienced hematologic adverse events related to LD chemotherapy. SynKIR-110 was quantified in peripheral blood and increased with dosage, reaching peak levels >20,000 copies/µg DNA in cohorts 2 and 3, approximately 7 days after cell infusion. Effector T cell cytokines including interferon-gamma and tumor necrosis factor-alpha, reached peak serum concentration between 7 and 14 days after treatment, consistent with expectations for CAR T class therapies. Tumor responses were seen in 4 of 9 patients, up to 47% reduction for 1 patient each in cohorts 1 and 2, and 2 patients in cohort 3, one of whom maintained an iRECIST partial response through 6 months of follow-up. SynKIR-110 mesothelin-targeted KIR-CAR treatment showed a favorable safety profile, with notable clinical activity in the first 3 of 6 planned dose cohorts, in heavily pretreated patients with refractory mesothelin-expressing advanced solid tumors. MTD was not reached and dose-escalation enrollment is ongoing in this phase 1 FIH trial. Funding: Verismo Therapeutics Citation Format: Janos L. Tanyi, Andrew Haas, Mark O'Hara, Zhubin Gahvari, Raed Al-Rajabi, Mehmet Altan, Daniel Sterman, Emily Winters, Andrea Campanile, Susan Howard, Raymond Luke, Tony Truong, Megan Blair, Nora Yucel, Jun Xu, Don L. Siegel, Carl H. June, Michael C. Milone, Laura A. Johnson. Initial results of a first in human dose-escalation study of KIR-CAR in patients with advanced mesothelin-expressing solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT104.