Promoting immunotherapy of cancer with focused ultrasound

Abstract

Immunotherapy (ITx) has revolutionized cancer treatment. Nonetheless, for several indications, many patients do not respond to ITx due to poor immune cell infiltration and/or limited ITx penetration into solid tumors. Both thermally ablative (T) and mechanical (M) forms of focused ultrasound (FUS) may be capable of overcoming these challenges. For example, the pre-clinical application of T-FUS in combination with myeloreductive gemcitabine elicits immunological control of 4T1 breast tumors and metastases, results that inspired the Br54 clinical trial for early stage breast cancer patients at UVA. Meanwhile, our Br48 clinical trial, which combines αPD-1 ITx with T-FUS in Stage III/IV breast cancer patients, shows that the well-tolerated treatment yields reduced regulatory T cells and transcriptional alterations consistent with inflammasome activation, interferon gamma signaling and αβ T cell activation. Regarding M-FUS, in pre-clinical brain tumor studies, we have used ImmunoPET imaging to optimize the timing of ITx antibodies (i.e., αCD47) administration with M-FUS-mediated blood-tumor barrier opening. This readily translatable treatment controlled GL261 tumors and improved survival markedly over previous studies that required multi-fold more αCD47 administration to achieve an effect. Overall, our pre-clinical and clinical results support the use of both T-FUS and M-FUS in combination with ITx for multiple cancer indications.