Paper Details

ABSTRACT

Introduction

SynKIR-310 is an autologous multi-chain killer immunoglobulin-like receptor (KIR)-based chimeric antigen receptor (KIR-CAR) T cell therapy targeting CD19-expressing B cell malignancies, designed with a separated antigen binding from activation signaling system associated with natural killer (NK) cells. SynKIR-310 comprises a canine-derived CD19-binding single-chain variable fragment (scFv) DS191 fused to KIR2DS2, which targets B cell-derived tumors, and signals via independent DAP12 protein, effectively separating antigen binding from T cell activation. This natural NK cell-derived signaling allows T cells to recover between tumor encounters. Compared with benchmark single-chain 2^nd generation CD19 CAR T, multi-chain SynKIR-310 achieves faster tumor regression and deeper tumor control with lower cytokine production in preclinical leukemia and lymphoma models (Blair et al, Cancer Res. 2026). Here we report initial clinical data from dose cohorts 1 and 2 of the CELESTIAL-301 trial, a Phase 1 multicenter dose-escalation study of SynKIR-310 in patients (pts) with relapsed or refractory B cell non-Hodgkin lymphoma (B-NHL) (NCT 06544265).

Methods

Eligible pts have relapsed/refractory B-NHL after ≥2 prior lines of therapy, measurable disease at enrollment, and an ECOG score of 0 or 1. This study employs a standard 3+3 dose escalation plus expansion design to explore up to 4 potential cell doses (cohort 1 = 1×10⁸, cohort 2 = 3×10⁸, cohort 3 = 1×10⁹, cohort 4 = 3×10⁹ ) of viable transduced SynKIR-310 cells following standard lymphodepletion with cyclophosphamide and fludarabine on outpatient or in-patient basis. The primary objectives are safety and identification of the recommended Phase 2 dose. Secondary and exploratory objectives include feasibility of cell product manufacture and administration, efficacy as assessed by objective response rate (ORR) per Lugano criteria by investigator review, and characterization of pharmacokinetics (PK) and pharmacodynamics (PD). The data cutoff date for this analysis was July 14, 2026.

Results

At data cut-off, 6 pts received SynKIR-310 infusion (3 in cohort 1 and 3 in cohort 2) with 3 pts receiving treatment in the outpatient setting. The median age was 72 years (range: 66-78) with 3 each male and female pts. Three pts had aggressive B-NHL subtypes including diffuse large B cell lymphoma or transformed follicular lymphoma (FL)/large B cell lymphoma, and 3 had indolent subtypes including marginal zone lymphoma (MZL) or FL. All 3 pts with aggressive subtypes had high-risk molecular profiles with double-hit or triple-hit disease. All pts had stage III/IV disease at baseline or screening, 4 pts (67%) were ECOG 1, and 3 pts (50%) had extranodal disease. One pt with MZL had persistent high-burden diffuse bone marrow involvement at screening. The median number of prior lines of therapy was 2 (range 2-4) and 1 pt had prior autologous stem cell transplant. Baseline lactate dehydrogenase was elevated in 4 pts (67%).

Treatment-related adverse events (AEs) considered possibly related to SynKIR-310 included headache (G1), hypogammaglobulinemia (G2), fatigue (G1), neutrophil count decrease (G4), and white blood cell decrease (G4), each in 1 pt.  There were no serious AEs related to SynKIR-310 and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was reported. No dose limiting toxicities were observed. Five pts were evaluable for efficacy at data cut-off. The ORR was 80% (4/5 pts) with a median time to response of 1 month, and 3/5 pts (60%) achieved complete response (CR), and the median duration of response in pts with CR was not reached with 1 pt in continued CR at their 12-month assessment.

Conclusion

Preliminary results demonstrate promising clinical activity in elderly, heavily pretreated pts with relapsed/refractory aggressive and indolent B-NHL. A key finding from early dose-escalation is that SynKIR-310 demonstrates clinical activity without the expected immune-mediated toxicities (e.g., CRS, ICANS) associated with approved single-chain CAR T-cell products at similar dose ranges. This profile may be particularly attractive for pts who are not well-suited to tolerate toxicities associated with available CAR T-cell therapies. Enrollment and follow-up are ongoing. Updated clinical and PK/PD correlative data across dose cohorts 1 through 3 will be presented at the conference.