557 Evaluation of huCART19-IL18 manufactured using Synecta™ CDNP technology to improve CAR-T yield and consistency in cohort D of an ongoing phase I study (NCT04684563)

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Background Chimeric antigen receptor (CAR) T cells targeting CD19 have demonstrated substantial efficacy in B-cell malignancies, though durable responses remain limited in many patients. huCART19-IL18 is a fourth-generation, CD19-directed CAR T cell therapy engineered to secrete interleukin-18 (IL-18) to enhance antitumor activity by engaging both innate and adaptive immunity. In Cohorts A-C of the ongoing Phase I study ( NCT04684563), huCART19-IL18 exhibited a manageable safety profile and encouraging antitumor activity in patients with relapsed or refractory non-Hodgkin lymphoma and chronic lymphocytic leukemia, as recently reported in NEJM.1 These cohorts employed a 3-day manufacturing protocol—significantly shorter than standard CAR T cell production timelines—which introduced challenges in consistently achieving target dose levels, particularly at higher planned dose cohorts.Methods Cohort D was initiated to evaluate a modified manufacturing process designed to improve cell expansion, transduction efficiency, and product consistency. The new process incorporates Synecta™ Cell-Derived Nanoparticles (CDNPs)—a novel activation technology displaying membrane-bound co-stimulatory molecules and cytokines—and performs lentiviral transduction on Day 0, immediately after activation. Synecta CDNPs are referenced in an FDA-reviewed Drug Master File. T cells undergo 3 days of expansion in a closed system. Final products are evaluated for transduction efficiency, expansion fold, viability, memory phenotype, and potency. Patients receive lymphodepletion prior to infusion. Pharmacokinetics (PK) of huCART19-IL18 in blood and bone marrow is being assessed post-infusion. Objectives are:• Primary: Assess feasibility and reproducibility of CAR-T cell Synecta-based manufacturing at clinical scale.• Secondary: Evaluate expansion yield, CAR expression, T cell phenotype, and in vivo kinetics in peripheral blood and bone marrow.Conclusions Two large-scale engineering runs using the Synecta-based process successfully met all release criteria and showed robust early expansion by Day 3. Cohort D is currently open and actively recruiting. No clinical data from this cohort have been reported to date.Trial Registration NCT04684563Reference Svoboda J, Landsburg DJ, Gerson J, Nasta SD, Barta SK, Chong EA, Cook M, Frey NV, Shea J, Cervini A, Marshall A, Four M, Davis MM, Jadlowsky JK, Chew A, Pequignot E, Gonzalez V, Noll JH, Paruzzo L, Rojas-Levine J, Plesa G, Scholler J, Siegel DL, Levine BL, Porter DL, Ghassemi S, Ruella M, Rech A, Leskowitz RM, Fraietta JA, Hwang WT, Hexner E, Schuster SJ, June CH. Enhanced CAR T-cell therapy for lymphoma after previous failure. N Engl J Med. 2025 May 8;392(18):1824-1835. doi: 10.1056/NEJMoa2408771. PMID: 40334157.

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