Novel SynKIR-310 outperforms CD3-based second-generation CD28 or 41BB co-stimulated CAR T in B-cell non-Hodgkin lymphoma xenograft mice and shows early clinical signal

Over half of B-NHL patients (pts) receiving FDA-approved CD19-targeting chimeric antigen receptor (CAR) T experience progressive disease within 1 year 1 , demonstrating need for more durable therapies. Unlike CD3-based single-chain CAR, killer immunoglobulin-like receptor (KIR)-based CAR have a multi-chain design derived from natural killer (NK) cells 2 with separated antigen binding and activation signals, and reduced tonic signaling and off-target activity 3 . SynKIR-310 is an autologous T cell therapy targeting CD19 with canine-derived single chain variable fragment (scFv), DS191. We previously compared SynKIR-310 to single-chain FMC63-41BBζ (tisagenlecleucel analog) for anti-tumor functionality in NALM6 B-cell leukemia-engrafted NOD-SCID-IL2Rgammac -/- (NSG) mice. SynKIR-310 showed faster tumor regression and increased tumor control with reduced systemic cytokines and comparable T cell persistence 4 . Here we evaluated SynKIR-310 in B-NHL Raji cell Burkitt lymphoma xenograft NSG mice compared with FMC63-41BBζ and single-chain FMC63-CD28ζ (axicabtagene ciloleucel analog). Mice were IV injected with Raji tumors and then IV injected with T cells. Tumor progression was monitored by bioluminescent imaging. In this Raji model, SynKIR-310 and FMC63-41BBζ showed comparable anti-tumor efficacy and increased overall survival, while FMC63-CD28ζ had no impact over negative control animals despite similar T cell persistence across groups. SynKIR-310 and FMC63-41BBζ produced similar levels of cytokines in vivo , while FMC63-CD28ζ produced significantly more cytokines at both early and late timepoints, despite worse tumor control. At the early timepoint, FMC63-CD28ζ produced 11-fold more IL-2 than SynKIR-310 and FMC63-41BBζ, while IFNgamma and TNFalpha were comparable across groups. At the late timepoint, FMC63-CD28ζ produced 11-fold more IFNgamma and 9-fold more TNFalpha, compared to SynKIR-310 and FMC63-41BBζ. SynKIR-310 achieves significantly improved tumor control compared to FMC63-CD28ζ in a Raji B-NHL mouse model, with reduced cytokine production. We have previously shown SynKIR-310 has superior anti-tumor efficacy over FMC63-41BBζ in a leukemia NALM6 model, here FMC63-41BBζ and SynKIR-310 had comparable anti-tumor efficacy against B-NHL Raji, though SynKIR-310 was the only group with 100% survival. These data support a potentially increased benefit-risk profile of SynKIR-310 compared with conventional CD3-based CAR T and merits further investigation in patients with B-NHL. We are enrolling pts in a Phase 1 first-in human multi-site U.S.-based clinical trial for relapsed/refractory B-NHL, including pts with or without prior exposure to CAR T (NCT06544265). Early clinical pt data will be presented. 1 Cappell KM Nat Rev Clin Oncol 2023 2 Wang E Cancer Immunol Res 2015 3 Yucel N JITC Nov 2025 Abst 298 4 Blair M Blood Dec 2025 Abst 4103