GK01 stemness-enriched tumor-reactive T-cell therapy plus IL-2 in advanced solid tumors: ORR and clonal persistence results in a first-in-human phase I study (GUARDIAN-01).

Abstract

2540 Background: T-cell exhaustion and poor persistence limit tumor infiltrated lymphocytes (TILs) efficacy in solid tumors. GK01 is an autologous tumor-reactive T-cell product enriched for stem cell memory T cells (TSCM: CD45RA + CD62L + ) and diverse T-cell receptor (TCR) clonotypes to promote durable engraftment. We conducted GUARDIAN-01 (NCT06954558), a phase I study of GK01 plus IL-2 in advanced solid tumors. Methods: This single-arm, open-label study enrolled patients with advanced solid tumors (ECOG PS 0-1; measurable disease per RECIST v1.1). Patients received standard lymphodepletion, GK01 (5×10 9 -1×10 11 cells per manufacturing yield), and IL-2 (300,000 IU/kg IV q12h, up to 5 days). Repeat infusion was permitted at investigator discretion based on clinical benefit. Primary endpoint was safety; secondary endpoints included objective response rate (ORR), disease control rate (DCR), and cellular kinetics via absolute lymphocyte count (ALC) and TCR sequencing. Results: From March 2025 to January 2026, 6 patients were enrolled (median age 53.5 years; median 2 prior lines; tumor types included gastric n = 3, pancreatic n = 1, penile SCC n = 1, and melanoma n = 1). Manufacturing succeeded in all patients; median time from tissue procurement to infusion was 28 days (range 25-39). Infused GK01 exhibited median TSCM frequency of 71% (range 42-92%) and demonstrated robust expansion and stemness properties. Upon tumor challenge, these T cells secreted IFN-γ at a median of 1,632 pg/mL (range, 35 - 4,886). Median dose was 2.8×10 10 cells (range 1.4×10 10 -8.8×10 10 ); 2 patients received repeat infusion. The median total IL-2 dose administered was 4 (range 1-5), with the first dose administered approximately 6 hours after GK01 infusion. No dose-limiting toxicities (DLTs) occurred. G3/4 adverse events were exclusively hematologic (neutropenia, thrombocytopenia, leukopenia, lymphopenia in all patients), attributable to lymphodepletion. Chills, fever, and erythroderma occurred in all patients but G1-2, resolving within 2 weeks. At median follow-up of 169 days (range 80-297), ORR was 66.7% (4/6 PR; 2/6 SD), and DCR was 100%. The median peak ALC reached at 11.3×10 9 /L (range 4.9-22.7) at days 7-9 post-infusion, remained elevated at 3.1×10 9 /L (range 2.0-6.4) at 1 month. Among patients with available peripheral-blood samples (n = 4), product-derived TCR clonotypes comprised 94% of the circulating repertoire at day 7 and 92% at 2 months. Conclusions: In this first-in-human study, GK01 plus IL-2 demonstrated a favorable safety profile with no DLTs and manageable toxicity. The TSCM-enriched product achieved a 67% ORR and 100% DCR, with product-derived clonotypes persisting at > 90% of the T-cell repertoire at 2 months. These findings validate the stemness-enriched T-cell platform and support expansion cohorts in selected solid tumor indications. Clinical trial information: NCT06954558 .