Stimulation of oncogene-specific tumor infiltrating T-cells through combined vaccine and alpha-PD1 enable sustained anti-tumor responses against established HER2 breast cancer (BC) [WXS]

This study demonstrates two fundamental tenets of immunotherapy: vaccines targeting any tumor antigen will not be as effective as those targeting true oncogenic drivers and neither the stimulation of tumor-specific T-cells nor the blockade of a key immune checkpoint is enough to overcome the layers of immune suppression by itself. It provides single cell genetic evidence that vaccination alone generates a population of CD8 T-cells incapable of long-term tumor control due to the activation of numerous immune dysfunction pathways within the tumor. These promising studies have led to the initiation of a Phase II clinical trial testing a novel HER2 vaccine in combination with Pembrolizumab (NCT03632941) to determine if this combination can elicit effective anti-tumor immunity while minimizing off-target immune responses in patients with advanced HER2+ BC. Overall design: This novel mouse model is driven by expression of an oncogenic isoform of HER2. To examine the mutation rate and neoepitope formation in these tumors, we performed paired bulk RNAseq/DNAseq of tumors to determine tumor mutational burden and neoepitope profiles in our mice.