Variety is the Spice of Sound: Intersection of Focused Ultrasound with Drug Delivery and Immunotherapy

Focused ultrasound (FUS) is currently poised to become a ubiquitous platform on which many disease therapies can be treated. FUS is being applied to everything from Alzheimer’s, essential tremor, uterine fibroids, bone metastases, breast cancer and melanoma at the preclinical and clinical level. With the maturation of the FUS field, more sophisticated questions and applications are being investigated. Questions pertaining to lifting pathological resistance mechanisms, combination therapies of FUS and chemo/immunotherapies and understanding fundamental immunological concepts are being interrogated. However, FUS does not come in one flavor and researchers have developed multiple FUS treatment schemes which can generate a plethora of biological effects. Though this increases the applicability of FUS as a disease treatment platform, this variability simultaneously increases the difficulty of investigation as well.

Thermal ablation: the hot sauce of FUS
Being the most widely used clinical FUS regimen, thermal ablation (TA), is well-positioned for rapid translation from a preclinical setting. In the cancer context, TA has made its impression on the field by using thermal accumulation to augment drug delivery and the tumor microenvironment (TME). The rationale for using TA to treat cancer in combination with chemo- and immunotherapies is that TA can increase the local dose of a therapy allowing clinicians to decrease systemic doses. By decreasing the systemic dose of therapies, patient side effects and off-target effects can be reduced. Consequently, studying how TA affects drug delivery of novel therapeutic constructs (e.g., liposomal formulations) is crucial. Herein, we investigated how TA alters liposomal delivery and therapeutic efficacy in breast cancer. In conclusion, we saw that TA massively increases drug delivery but did not increase therapeutic efficacy. However, increases in drug delivery are not the only effects of TA on cancer
Researchers are now using TA to remodel the TME to promote anti-tumor immune responses. The emergence of paradigm of “cold” vs “hot” tumors has revolutionized cancer therapy. We, including many others, hypothesize the inflammation induced by TA in the TME can push a “cold” tumor (i.e., poorly immune infiltrated tumor) toward a “hot” tumor (i.e., well infiltrated tumor with effector cells). Therefore, understanding how TA alters the intratumoral transcriptome and immune cell representation and function is essential for translation to patient care. This line of research will enable researchers to make rationale combinatorial therapy strategies to optimize patient responses. We show that TA appears to transiently alter the intratumoral transcriptome and the immune landscape in favor of granulocyte recruitment.

Boiling histotripsy: bubbly destruction
Boiling histotripsy (BH) elicits biological effects in a vastly different way than TA. BH mechanically homogenizes by generating bubble cavitation in the targeted tissue without the adverse side effect of thermal accumulation to surrounding, untargeted tissues. This form of FUS is relatively new and understudied compared to TA. Furthermore, the electronics to drive BH are more complex and expensive with far more nuance in how BH is applied. However, research on BH effects on cancer is on the upsurge. BH holds great promise as a cancer therapy as initial BH studies have shown that BH shifts the TME away from a pro-tumor phenotype towards an anit-tumor phenotype in mice. Nevertheless, massive gaps in our knowledge about its mechanism for altering immune responses exist. As clinical trials using BH begin, we need to fill in these knowledge gaps. We explored the antigen drainage component of cancer immunity. BH massively increases antigen acquisition by phagocytic and antigen presenting cells while also increasing their activation/maturation.