Background: LAVA-1207 is a humanized bispecific antibody of 78 kDa comprised of two single domain antibody (VHH) fragments linked to a silenced fragment crystallizable immunoglobulin region. As shown pre-clinically, LAVA-1207 binds with high affinity to the Vδ2 chain of Vγ9Vδ2-T cells, a potent immune effector cell population, and to prostate specific membrane antigen (PSMA) expressed by prostate cancer cells to trigger robust (pM range EC₅₀) Vγ9Vδ2-T cell mediated lysis of prostate cancer cells, whereas normal cells are relatively spared. Based on earlier clinical experience with systemic activation of Vγ9Vδ2-T cells through aminobisphosphonates and in vivo studies in non-human primates with cross-reactive surrogate bispecific γδ-T cell engagers, a low risk for cytokine release syndrome (CRS) is expected in the clinic. Methods: This is an open label, 3+3 design, phase 1/2a study in patients with therapy refractory metastatic castration resistant prostate cancer (NCT05369000; EudraCT Number: 2021-001789-39) to determine the safety of LAVA-1207 and its recommended Phase 2a dose (RP2D) and schedule. Secondary objectives include evaluation of PK, PD, immunogenicity, and preliminary antitumor activity. LAVA-1207 is administered IV every two weeks with an infusion duration of 2 hours for the first dose, 1 hour for the second dose, and 30 minutes for all subsequent doses. Results: As of September 23, 2022, a dose level of 40 µg (starting dose was 1.5 µg based on MABEL approach) has been reached without dose limiting toxicities (DLTs). A total of 16 patients have been treated with LAVA-1207 with treatment duration ranging from 1 to 25+ weeks. Treatment emergent AEs (TEAEs) that were suspected to be related were all grade 1-2, and included nausea (n=3), AST increase (n=2), fatigue (n=2), and infusion related reaction (n=2). Severity of TEAEs did not increase with escalating doses and no patient discontinued treatment due to an AE. PK data indicate increasing drug exposure in correlation with increasing doses of LAVA-1207. PD data show a consistent early reduction in Vγ9Vδ2-T cell frequencies at 2hrs after the first dose, which could be indicative of Vγ9Vδ2-T cell redistribution after treatment, often accompanied by an increase in Vγ9Vδ2-T cell activation markers. Vγ9Vδ2-T cell numbers are restored in the subsequent 3 to 5 days to at least pre-dose levels. Additionally, receptor occupancy of Vγ9Vδ2-T cells was detectable up to 5 days after first dosing. To date, stable disease at 8 weeks has been observed in 3 out of 8 evaluable patients. Conclusions: LAVA-1207 has been well tolerated early in dose escalation; further clinical activity including PSA results, response assessment, and pharmacodynamic data will clarify determination of an optimal biological active dose. Clinical trial information: NCT05369000.