Highlights of This Issue

Abstract

T cell-dependent bispecific antibodies (TDBs) form immunological synapses between cancer cells and T cells. Cancer cell killing is achieved when the bispecific antibody simultaneously binds a cancer cell surface antigen and T cell receptors, such as CD3. Here, Mandikian and colleagues determine the impact of CD3 affinity on tissue distribution and catabolism of TDBs in vivo using huCD3 transgenic mice containing huHER2 tumors. Higher CD3 affinity drives TDBs away from tumors, while increasing distribution and catabolism in secondary lymphatic tissues. These results may warrant affinity balance, instead of affinity maturation, for strategic development of T cell-dependent bispecific antibody therapeutics.Most patients with advanced non-small cell lung cancer (NSCLC) fail to achieve long-term survival with conventional treatments, such as chemotherapy and radiotherapy. Here, Pitroda, Stack and colleagues report a novel application for the selective JAK2 inhibitor SAR302503 (SAR) in therapy resistant NSCLC. The authors found that constitutive interferon-stimulated gene expression identifies a subgroup of NSCLCs that is resistant to genotoxic therapies, but sensitive to SAR. Importantly, SAR also abrogates interferon-induced PD-L1 expression linked to immunosuppression. These results may lead to improved treatment strategies for NSCLC by utilizing JAK2 inhibitors either as a monotherapy or in tandem with immune checkpoint inhibition.Multiple epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have been developed to effectively inhibit EGFR-derived signals in non-small cell lung cancer (NSCLC). In this study, Hirano and colleagues assessed the efficacy of naquotinib (ASP8273), a novel third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) in several clinically relevant EGFR mutations. Using structural analyses, they further elucidated the mechanism of activation and sensitivity/resistance to EGFR-TKIs in EGFR exon 20 insertion mutations. Their findings are important in the selection of appropriate EGFR-TKIs for the treatment of NSCLC with EGFR mutations, and provide more insight to the biology of EGFR exon 20 insertion mutations.Carbon ion therapy (CIT) is an important emerging cancer treatment as it is more biologically effective than conventional X-ray radiation. While the impact of CIT on cell lines and transplant tumor models has been studied at Asian and European centers, the effects on primary tumor models were previously unknown. To better understand how CIT impacts autochthonous tumors, we developed a CIT platform at a US research laboratory and irradiated primary sarcomas with either CIT or X-rays. We found that CIT was more potent than anticipated and noted unexpected and important differences on tumor growth and immune response with this modality.