Phase I dose escalation of LAVA-051, a novel bispecific gamma-delta T-cell engager (Gammabody), in relapsed/refractory hematological malignancies.
Authors: Broijl Annemiek , van de Donk Niels W.C.J. , Bosch Francesc , Mateos Maria-Victoria , Rodríguez-Otero Paula , Tucci Alessandra , Ghia Paolo , Adang Anton EP , Parren Paul WHI , Tuinhof Ilse , Umarale Sanjana , Winograd Benjamin , van der Vliet Hans J. , Kater Arnon P. 
Published: June 2022

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Background: LAVA-051 is a 27kD humanized bispecific single domain antibody (VHH) that directly engages CD1d and the Vδ2-TCR chain of Vγ9Vδ2-T cells and additionally stabilizes the interaction between CD1d and type 1 NKT cells (Nature Cancer 2020;1:1054-1065) to mediate potent killing of CD1d-expressing tumor cells. By engaging innate-like T cell subsets with inherent antitumor activity, namely Vγ9Vδ2-T and type 1 NKT cells, LAVA-051 has the potential to combine high therapeutic efficacy with limited off-tumor toxicity. CD1d is expressed by tumor cells in the majority of patients with CLL (chronic lymphocytic leukemia) and MM (multiple myeloma), while expression in AML (acute myeloid leukemia) is most pronounced on (myelo)monocytic subtypes. Tolerability studies in non-human primates with cross-reactive surrogate bispecific γδ-T cell engagers showed a good safety profile without signs of CRS (cytokine release syndrome). Methods: This is an open label, accelerated titration design, phase 1/2a study in patients with relapsed/ refractory CLL, MM, and AML (NCT04887259). The phase 1 study starts with single-patient cohorts for the first 3 dose levels followed by a 3+3 design. The primary objectives of the study are to investigate the safety and tolerability of LAVA-051 and to determine its recommended Phase 2a dose (RP2D). Secondary objectives of the study include evaluation of PK, PD, immunogenicity, and preliminary antitumor activity. The (flat) starting dose was determined to be 0.45 µg. LAVA-051 is administered by IV infusion over 2 hours twice a week. Results: As of Feb 14, 2022, a dose level of 45 µg has been reached with no reports of CRS (ASTCT grading) or dose limiting toxicities (DLTs). Six patients in total have been treated with LAVA-051; 4 patients (2 MM, 2 CLL) were evaluable for DLTs during cycle 1 at dose levels 0.45 µg, 3 µg, 15 µg and 45 µg. Treatment emergent AEs (TEAEs) (CTCAEv5.0) were predominantly of grade 1 and 2 severity (e.g. fever, chills, and headache). One patient (45 µg) reported a grade 2 infusion related reaction (IRR) that lasted less than 12 hours following the first administration only. Frequency and severity of TEAEs did not increase with escalating doses and all TEAEs were reversible. One patient with CLL developed symptoms consistent with a tumor flare reaction during cycle 1, and continues on cycle 5 of treatment with stable disease at 15 µg. PK data indicate increasing drug exposure in correlation with increasing doses of LAVA-051, and PD data indicate a dose-dependent increase in LAVA-051 receptor occupancy of the Vγ9Vδ2-T cell receptor. Importantly, no consistent or significant changes in measured cytokines have been observed. Updated results will be presented at the congress. Conclusions: LAVA-051 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with Vγ9Vδ2-T cell engagement. Clinical trial information: NCT04887259.