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ErbB3 activation leads to resistance to EGFR inhibition in cancer, and the ErbB3 ligand neuregulin-1 (NRG1) is expressed in most head and neck squamous cell carcinomas (HNSCC). Duvvuri and colleagues conducted a window-of-opportunity trial in HNSCC patients to characterize the biologic activity of CDX-3379, a human anti-ErbB3 monoclonal antibody. CDX-3379 modulated pErbB3 in tumors and led to a marked clinical response in a subset of patients. These data provide the rationale for further development of CDX-3379 in HNSCC and additional ErbB3-/NRG-expressing tumor types.Malignant pleural mesothelioma (MPM) is a rare but lethal cancer. In a Phase Ib trial, Hassan and colleagues assessed the combination of pemetrexed and cisplatin with CRS-207, a live-attenuated Listeria monocytogenes vaccine expressing the mesothelin antigen in mesothelioma. This combination altered the tumor microenvironment to increase anti-tumor immune cells. Moreover, objective tumor responses were observed in most patients, with 89% demonstrating either complete response, partial response, or stable disease. These results support further clinical examination of the combination of chemotherapy and immune therapy in mesothelioma.Naturally occurring canine lung cancer shares many features with human disease, particularly in never-smokers. The molecular mechanisms of canine lung carcinogenesis, however, have not been assessed. Lorch and colleagues assessed the genomic landscape of canine lung cancer and found recurrent HER2 mutations in canine pulmonary adenocarcinoma, but not in adenosquamous or squamous cell carcinomas. The majority of the HER2 mutations observed were the V659E hotspot mutation that commonly occurs in human disease. These results further confirm naturally occurring canine lung adenocarcinoma as a comparable model to human lung cancers in never-smokers.4-1BB is a key costimulatory immunoreceptor which enhances cytolytic activity of T and NK cells when activated. Attempts to agonize the pathway via conventional antibodies, however, have been hampered by peripheral toxicity. To facilitate tumor-localized T-cell costimulation, Hinner and colleagues synthesized PRS-343, a 4-1BB/HER2 bispecific molecule. PRS-343 led to effective 4-1BB-mediated costimulation of T cells in vitro in the presence of HER2-positive cancer cells. In a humanized mouse model, PRS-343 treatment led to tumor growth inhibition and a dose-dependent increase of tumor-infiltrating lymphocytes. These data support the clinical trials now underway assessing the efficacy and safety of PRS-343.