Tuning Tumor Vasculature to Amplify Focused Ultrasound Therapy

One promising class of anti-cancer drugs—immunotherapy—often extends patient survival, but fails to significantly improve the cure rate of solid cancers. In tumor types which are more refractory to these treatments, inherent tumor properties often prevent a sufficiently powerful anti-tumor immune response. And in tumor types which typically respond well, some patients still respond poorly to immunotherapy. Given the simultaneous promise and patient response heterogeneity of immunotherapy, novel approaches to improve immunotherapy’s efficacy are necessary. One intervention that may enhance the effects of immunotherapy is focused ultrasound (FUS). FUS, which can deposit concentrated sound energy into tumor tissue in a non-invasive, non-ionizing manner, induces bioeffects ranging from blood vessel disruption to thermal ablation. We argue that two FUS modalities could render immunotherapy more effective: mechanical FUS (mFUS) and thermally ablative FUS (tFUS). mFUS has been shown to augment local drug delivery, and we expect its application to solid tumors to augment local delivery of immunotherapy. tFUS has been shown to ablate solid tumors, inducing immune reactions and temporary tumor control, which we anticipate will enhance the effects of immunotherapy. We therefore hypothesize that both mFUS and tFUS can augment the efficacy of immunotherapy. However, we anticipate the efficacy of both immunotherapy and tFUS is limited by tumor blood vessels—solid tumors vasculature is systematically dysfunctional compared to that of healthy tissue. Pro-angiogenic signaling is a primary culprit of tumor vessel dysfunction, and pharmaceutically blocking this signaling has been found to temporarily improve tumor vessel function in a phenomenon known as “vascular normalization”. Since vascular normalizing drugs can improve both drug delivery and immune-related metrics within tumors, we expect them to enhance the effects of both mFUS and tFUS. We combine vascular normalization (VN) with both mFUS and tFUS in this dissertation and find enhances the effects of both FUS modalities. Using MRI T1-mapping to quantify model drug delivery in a murine triple-negative breast cancer model, we find that the ability for VN and mFUS to boost drug delivery depends on drug size. The delivery of small, chemotherapy-sized model drugs is additively enhanced with VN and mFUS, with the combination improving drug dispersion throughout the tumor. The delivery of larger, biologic-sized model drugs is synergistically augmented with VN and mFUS. Combining VN and tFUS to treat murine triple-negative breast cancer, we find that the combination synergistically eradicates tumors and prevents tumor growth when mice are rechallenged with tumors, which we determine is T cell-dependent. After adding anti-PD1—a common immunotherapy—to VN and tFUS, we observe an even greater anti-tumor response. This dissertation confirms that vascular modulation with anti-angiogenic drugs can improve the efficacy of FUS, both in augmenting drug delivery and in inducing long-term immune responses with ablation. Not only is this the first work to combine FUS and vascular normalization, it also paves the way for novel combinations of both therapies in clinical settings.