Selected Articles from This Issue

Most anti-PD1/PD-L1 antibodies have exhibited poor efficacy in some clinical indications, primarily due to insufficient infiltration of immune cells into the tumor microenvironment (TME). This study presents a novel biological mechanism for the design of an Fc-silenced anti-PD-L1/OX40 bispecific antibody (EMB-09), which aims to augment both peripheral and tumor-associated immune responses, thereby enhancing anti-tumor immunity. Through these mechanisms, EMB-09 has demonstrated superior anti-tumor activity compared to anti-PD-L1 monotherapy in preclinical animal models and has shown preliminary efficacy in early-phase clinical trials. The findings from this study could provide significant insights into cancer immunotherapy by modulating peripheral immune responses beyond the tumor microenvironment.T cells in the tumor microenvironment require peptide-MHC–T Cell Receptor interaction (Signal 1) coupled with costimulatory receptor engagement (Signal 2) for optimal activation. Because tumors often lack natural costimulatory ligands, a tumor-specific Signal 1 in the absence of Signal 2 may be ineffective or even induce T cell anergy. Here, Moore and colleagues characterize the costimulatory properties of XmAb808, a B7-H3×CD28 bispecific antibody that conditionally activates T cells only in the presence of Signal 1 plus B7-H3-expressing tumor cells. XmAb808 stimulates efficient T cell-mediated cancer-cell killing in vitro and in humanized mouse models, supporting its clinical development as a solid-tumor immunotherapy.MAPK signaling is dysregulated in as much as one third of all human cancers, and there remains a significant unmet need to target oncogenes in this pathway therapeutically. Migoprotafib is a potent and selective Src homology-2 domain–containing phosphatase 2 inhibitor (SHP2) inhibitor designed to be combined with other MAPK-pathway strategies, including commercially available agents targeting KRAS and BRAF, to achieve longer lasting and more potent inhibition of these tumors. In this study we assessed migoprotafib in a dose-escalation and dose-expansion phase I study in advanced/metastatic solid tumors. We defined the recommended phase 2 dose (60 mg), described its safety and tolerability, and demonstrated convincing MAPK modulation downstream of RAS.Similarities in biology and treatment response of malignant cancers in dogs and humans underscore the potential merit of a comparative oncology approach for critically evaluating novel immunotherapeutic strategies. Here, we investigated an intratumoral anchored IL-12 technology (JEN-101) in dogs with advanced melanoma as a translationally relevant prologue to a first-in-human clinical trial (NCT06171750). In dogs with melanoma shaped under natural immunosurveillance mechanisms, JEN-101 was well-tolerated and generated robust immune activation and therapeutic efficacy in responders. These results highlight the clinical potential of intratumoral anchored IL-12 technologies for improving treatment outcomes in comparative melanocytic pathologies affecting human cancer patients.