Lava-051, a Novel Bispecific Gamma-Delta T-Cell Engager (Gammabody), in Relapsed/Refractory MM and CLL: Pharmacodynamic and Early Clinical Data

Abstract

Background: LAVA-051 is a Vγ9Vδ2-T cell engaging bispecific antibody of 27 kDa that directly engages tumor expressed CD1d and the Vδ2-TCR chain of Vγ9Vδ2-T cells to kill tumor cells in a tumor target-dependent manner. Binding between LAVA-051 and CD1d also causes the activation of a second effector cell type: invariant natural killer T (iNKT) (Nature Cancer 2020;1:1054-1065). By dual engagement of these unique innate-like T cell subsets with inherent antitumor activity, LAVA-051 has the potential to exhibit high potency antitumor activity. Based on clinical experience with systemic activation of Vγ9Vδ2-T cells through aminobisphosphonates and in vivo studies in non-human primates (NHP) with a surrogate CD1d-γδ T cell engager, a low risk for cytokine release syndrome (CRS) is expected. 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. The local tolerance of subcutaneous (SC) administration of LAVA-051 was studied in a NHP model with no signs of local intolerance or histopathological abnormalities observed. Methods: An open label, accelerated titration design, phase 1/2a study in patients with relapsed/ refractory CLL and MM (NCT04887259) is ongoing to determine the safety of LAVA-051 and its recommended Phase 2a dose (RP2D). Adverse Events (AEs) are graded per CTCAE V5.0 criteria and CRS is graded per ASTCT criteria. IMWG criteria (MM) and iwCLL guidelines (CLL) are used for disease evaluation. The RP2D will be the optimal biological active dose, supported by a panel of specific pharmacodynamic assays to determine the pattern of change in the binding of LAVA-051 to peripheral blood Vγ9Vδ2-T cells (i.e. Vγ9Vδ2-TCR occupancy), and in the frequency and activation status of Vγ9Vδ2-T and iNKT cells in circulation. LAVA-051 is administered by IV infusion over 2 hours twice a week or by SC administration; observation of changes in PD parameters following SC administration as compared to IV infusion will enhance selection of RP2D administration and schedule. Results: As of July 25, 2022, a dose level of 100 µg has been reached (starting dose 0.45 µg) with no reports of CRS or dose limiting toxicities (DLTs). Eight patients in total have been treated with LAVA-051; 4 patients with MM and 4 patients with CLL with treatment duration range of 1.6 to 18.1 weeks. Treatment emergent AEs (TEAEs) were predominantly of grade 1 and 2 severity, with a minority of AEs observed across more than one dose level: lymphadenopathy, pyrexia (underlying causes different from CRS), epistaxis, dyspnea, and leukopenia. Severity of TEAEs did not increase with escalating doses and no patient discontinued treatment due to an AE. Disease stabilization has been observed in two patients. Despite no observation of formal response, lymph node shrinkage was observed in one CLL patient and decreasing M-protein levels in one MM patient. Pharmacodynamic data reflect changes as expected per LAVA-051 mechanism of action (MoA): Vγ9Vδ2-T cell activation markers (CD25 and CD69) were consistently upregulated in each dose cohort where this could be assessed, maximum measured Vγ9Vδ2-T cell receptor occupancy increased with higher dose cohorts, and iNKT cell activation was observed. Furthermore, no significant increases in IL-6 or other CRS-related cytokines have been observed. Pharmacokinetic data indicate predictable and linear pharmacokinetics. Updated safety, PD, and PK results following IV and SC administration will be presented at the congress. Conclusions: LAVA-051 has been well tolerated early in dose escalation with pharmacodynamics and early clinical signs reflective of its intended MoA. The differentiating importance of these pharmacodynamic parameters with any correlating preliminary antitumor activity will be further elucidated with continued dose escalation by the IV and SC route and in the determination of the RP2D and schedule.