Abstract CT028: Results of first-in-human, Phase 1 study of KSQ-001EX, an autologous tumor infiltrating lymphocyte therapy engineered to inactivate the SOCS1 gene, in patients with select advanced solid tumors

Abstract KSQ-001EX is an engineered TIL (eTIL) therapy with CRISPR/Cas9-mediated inactivation of SOCS1, a negative regulator of cytokine signaling and T cell function. SOCS1 was identified in a series of genome-wide in vivo screens where inactivation of SOCS1 strongly enhanced the anti-tumor functionality of adoptively transferred tumor-specific CD8+ T cells, including engraftment, tumor infiltration, persistence, cytotoxicity and IFNγ production in preclinical models. This phase 1/2, single-arm, open-label, study is the first-in-human clinical study of KSQ-001EX (NCT06237881) evaluating the safety, tolerability, and efficacy of KSQ-001EX in patients with solid tumors. KSQ-001EX was manufactured from patient tumors collected through either surgical resection or core needle biopsies. Patients received lymphodepleting chemotherapy (LDC) with cyclophosphamide and fludarabine followed by a single infusion of KSQ-001EX. In the phase 1 safety lead-in, patients were dosed without IL-2 (Cohort 1) or with up to six doses of IL-2 (600,000 IU/kg) starting on day 1 post infusion (Cohort 2). The dose limiting toxicity (DLT) monitoring period was 28-days post KSQ-001EX administration. KSQ-001EX was directly tracked in the peripheral blood and tissue via detection of indels in the SOCS1 gene locus. As per the data cut off of 4 September 2025, KSQ-001EX was administered to 12 patients (Cohort 1, n=4: Cohort 2, n=8) with advanced melanoma who had progressed following ≥1 line of prior systemic therapy including treatment with anti-PD-1/PD-L1 (median lines of prior therapy, 2 [range, 1-5]). KSQ-001EX was infused at a target dose range of 1-10e9 cells (median cell dose 5.25e9). Two patients were dosed with 1 pt: hypertension, hyponatremia, hypoxia [n = 2 each]). Irrespective of IL-2 administration, in patients receiving >5.25e9 cells (n=6), 2 patients experienced a partial response, and one patient experienced stable disease for >1 year with continued reduction of tumor burden. KSQ-001EX consistently achieved a high level of on-target editing efficiency (>90%) and comprised predominantly of CD8+ T-cells (avg. 88±9%). KSQ-001EX displayed favorable engraftment, expansion, and persistence in the peripheral blood and tumor homing as assessed four weeks post-infusion. Consistent with the biology of SOCS1 edited TIL, elevated serum IFNγ levels (median peak 276 pg/mL [range 69-1530]) were observed in most patients independent of IL-2 dosing. Data from the phase 1 portion of the study demonstrates that KSQ-001EX has a manageable safety profile regardless of IL-2 administration, favorable kinetics and encouraging preliminary anti-tumor activity even at low cell doses (