The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early res Show more
The success of cancer immunotherapies is predicated on the targeting of highly expressed neoepitopes, which preferentially favours malignancies with high mutational burden. Here we show that early responses by type-I interferons mediate the success of immune checkpoint inhibitors as well as epitope spreading in poorly immunogenic tumours and that these interferon responses can be enhanced via systemic administration of lipid particles loaded with RNA coding for tumour-unspecific antigens. In mice, the immune responses of tumours sensitive to checkpoint inhibitors were transferable to resistant tumours and resulted in heightened immunity with antigenic spreading that protected the animals from tumour rechallenge. Our findings show that the resistance of tumours to immunotherapy is dictated by the absence of a damage response, which can be restored by boosting early type-I interferon responses to enable epitope spreading and self-amplifying responses in treatment-refractory tumours. Show less
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less