Metastasis is the main cause of morbidity and mortality in breast cancer. Triple negative (ERa- PR-Her2-) breast cancer (TNBrCa) has the lowest five year survival of all breast cancer subtypes, primarily due to the lack of effective therapy for disseminated disease. One feature of metastatic TNBrCa lesions is an increased level of MYB, an oncogenic transcription factor (TF). MYB is a stem cell related TF that drives proliferation and suppresses differentiation.
Whilst located within the nucleus MYB, like all other endogenous proteins, is processed and presented via MHC class I on tumour cells. Thus by breaking tolerance, it is possible to target this oncogene through a type 1 immune response. To achieve this we have created a DNA vaccine encoding two immunodominant, promiscuous tetanus peptides (P2 and P30) that flank a full length cDNA of MYB. This design bypasses MHC restriction by allowing all possible epitopes to be expressed.
Previous studies by our group have indicated a significant level of tumour control can be achieved with vaccine alone. Given the recent development and clinical results using antibody based checkpoint inhibitors such as anti-PD1, we have combined immune check point modulation with our vaccine in the metastatic triple negative 4T1.2 syngeneic mouse model to determine whether we can further increase therapy. This tumour metastasises spontaneously to bone, lungs and liver, therefore providing a clinically relevant model.