Search

Despite the success of programmed cell death-1 (PD-1) and PD-1 ligand (PD-L1) inhibitors in treating solid tumors, only a proportion of patients respond. Here, we describe a first-in-class bifunctional therapeutic molecule, STAR0602, that comprises an antibody targeting germline Vβ6 and Vβ10 T cell receptors (TCRs) fused to human interleukin-2 (IL-2) and simultaneously engages a nonclonal mode of TCR activation with costimulation to promote activation and expansion of αβ T cell subsets expressing distinct variable β (Vβ) TCR chains. In solution, STAR0602 binds IL-2 receptors in cis with Vβ6/Vβ10 TCRs on the same T cell, promoting expansion of human Vβ6 and Vβ10 CD4+ and CD8+ T cells that acquire an atypical central memory phenotype. Monotherapy with a mouse surrogate molecule induced durable tumor regression across six murine solid tumor models, including several refractory to anti–PD-1. Analysis of murine tumor-infiltrating lymphocyte (TIL) transcriptomes revealed that expanded Vβ T cells acquired a distinct effector memory phenotype with suppression of genes associated with T cell exhaustion and TCR signaling repression. Sequencing of TIL TCRs also revealed an increased T cell repertoire diversity within targeted Vβ T cell subsets, suggesting clonal revival of tumor T cell responses. These immunological and antitumor effects in mice were recapitulated in studies of STAR0602 in nonhuman primates and human ex vivo models, wherein STAR0602 boosted human antigen-specific T cell responses and killing of tumor organoids. Thus, STAR0602 represents a distinct class of T cell–activating molecules with the potential to deliver enhanced antitumor activity in checkpoint inhibitor–refractory settings. Editor's summary: Activating T cells by targeting T cell receptors (TCRs), costimulatory receptors, or cytokine receptors represents an attractive approach to improving antitumor T cell responses; however, these approaches often do not sufficiently stimulate T cell responses and can cause severe toxicities that have impeded their translation into the clinic. To address this, Hsu et al. developed a bifunctional therapeutic molecule called STAR0602, comprising an antibody specific to human TCR Vβ6 and Vβ10 chains fused to a human interleukin-2 (IL-2) molecule, which selectively activates a subset of T cells through both the TCR and IL-2 receptor signaling pathways. STAR0602 promoted specific expansion of human Vβ6- and Vβ10-expressing T cells and promoted killing of human tumor organoids in vitro. In vivo studies showed that a murine surrogate molecule promoted durable control of tumor burden in six solid tumor models. These data, along with favorable safety data, support further development of STAR0602 and similar TCR-targeting antibody fusion molecules. —Courtney Malo [ABSTRACT FROM AUTHOR]

Atezolizumab, a humanized monoclonal antibody against programmed cell death ligand 1 (PD‐L1), was initially approved in 2016, around the same time that the sponsor published the minimum serum concentration to maintain the saturation of receptor occupancy (6 μg/mL). The initially approved dose regimen of 1200 mg every 3 weeks (q3w) was subsequently modified to 840 mg q2w or 1680 mg q4w through pharmacokinetic simulations. Yet, each standard regimen yields steady‐state trough concentrations (CMIN,SS) far exceeding (≈ 40‐fold) the stated target concentration. Additionally, the steady‐state area under the plasma drug concentration–time curve (AUCSS) at 1200 mg q3w was significantly (P =.027) correlated with the probability of adverse events of special interest (AESIs) in patients with non‐small cell lung cancer (NSCLC) and, coupled with excess exposure, this provides incentive to explore alternative dose regimens to lower the exposure burden while maintaining an effective CMIN,SS. In this study, we first identified 840 mg q6w as an extended‐interval regimen that could robustly maintain a serum concentration of 6 μg/mL (≥99% of virtual patients simulated, n = 1000), then applied this regimen to an approach that administers 2 "loading doses" of standard‐interval regimens for a future clinical trial aiming to personalize dose regimens. Each standard dose was simulated for 2 loading doses, then 840 mg q6w thereafter; all yielded cycle‐7 CMIN,SS values of >6 μg/mL in >99% of virtual patients. Further, the AUCSS from 840 mg q6w resulted in a flattening (P =.63) of the exposure–response relationship with adverse events of special interest (AESIs). We next aim to verify this in a clinical trial seeking to validate extended‐interval dosing in a personalized approach using therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]