TPS2687 Background: In recent years, T-cell enhancement strategies have achieved notable survival benefits in patients with cancer. While cytokine therapy with both IL-2 and IL-21 demonstrate anti-cancer activity through enhanced proliferation, survival and function of antigen specific CD8+ T cells, their use is limited by off-target effects and rapid clearance. AB821 is a fusion of a CD8-targeting antibody that binds to the CD8αβ heterodimer on CD8+ T cells and an IL-21 mutein containing a mutation that attenuates affinity for the IL-21receptor. In pre-clinical experiments, AB821 promotes CD8+ T-effector cell cytotoxicity and CD8+ T-cell memory and demonstrates both robust tumor growth inhibition and minimal toxicity in immune checkpoint inhibitor refractory tumor models. Notably, AB821 avoids activation of other IL-21R-expressing cell types, including CD4+ T cells, NK cells, B cells, dendritic cells, intermediate monocytes, and nonclassical monocytes, that can act as pharmacologic sinks or contribute to off-target toxicity. Methods: This first-in-human phase 1 dose-escalation clinical trial is designed to assess the safety, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary anti-tumor activity of AB821 monotherapy administered every 2 weeks (Q2W) in patients (pts.) with recurrent locally advanced or metastatic melanoma and other immune-responsive solid tumor malignancies. Pts. with melanoma are required to have previously been treated with an inhibitor of PD1/L1 while pts. with other cancer types are required to have received a previous systemic treatment regimen. The primary objective of the study is to assess the safety and tolerability of AB821 and identify a candidate recommended phase 2 dose for further evaluation. AB821 is being administered as a 30-minute IV infusion on day 1 of each 2-week treatment cycle with therapy continued for a maximum duration of two years (52 cycles) or as long as participants experience clinical benefit as determined by the treating investigator. Dose-escalation and/or de-escalation decisions is being guided by a BF-BOIN design (Liu 2015; Yuan 2016) employing a target toxicity probability of 0.30 with up to 20 total pts. enrolled in backfill cohorts at the RP2D or lower dose levels determined by the investigators to be potentially efficacious in order to better assess the drug’s safety and efficacy. Accrual is ongoing. Specific dose levels and inclusion/exclusion criteria will be presented. Clinical trial information: NCT07027488 .
Kluger et al. (Thu,) studied this question.