Histotripsy: New technology making waves in IO

4777
Mina S Makary

Mina S Makary, assistant professor at the Division of Vascular and Interventional Radiology/Department of Radiology at the Ohio State University Wexner Medical Center (Columbus, USA) and collaborator Warren A Campbell IV from Ohio State University’s medical scientist training programme share their take on the impact histotripsy stands to make on the ablation space within interventional oncology (IO).

Ablation techniques utilise thermal stress to induce cell death, which is accomplished using currents, cryotherapy, microwaves, lasers, or ultrasound. While effective, these ablation techniques have limitations. Transducer placement requires percutaneous or laparoscopic access. Reliance on temperature can prevent effective targeting near sensitive structures, and uniform necrosis often cannot be achieved because of the heat-sink effect near vascular structures. The advent of histotripsy as an ablative modality has the potential to cause a shift in ablation therapies by addressing existing limitations. Histotripsy creates targeted cavitations with large amplitude pulses to mechanically disintegrate tissue1—cavitations are transient steam-filled microbubbles that form when high amplitude waves travel through fluid. Rapid expansion and implosion during cavitation causes significant sheer stress to break cells into subcellular components.

Histotripsy has technical advantages over traditional ablation methods. First, renal, hepatic, and intracranial masses can be targeted transdermally. Second, the primary mechanism is mechanical tissue destruction, which improves accuracy and focus on smaller targets.2 Third, connective tissue is more resistant to histotripsy, reducing the likelihood of collateral damage to blood vessels or biliary structures.3 Lastly, the area of destruction creates hypoechogenicity which is efficient to monitor in real time.4 With the principles of histotripsy, there exists the potential to target any tissue in the body for ablation in a precise, rapid approach, sparing non-targeted tissue and without percutaneous incisions or forms of dangerous ionising radiation.

Histotripsy is showing promise in the treatment of cancer. Preclinical animal studies demonstrated histotripsy’s ability to treat liver, prostate, breast, kidney, oesophageal, pancreas, and brain tumours through necrosis.5 For metastatic tumours, data have also detected an abscopal effect, where untargeted tumours decrease in growth rate. Targeted ablation disrupts the tumour’s evasion of the immune system. Mechanical perturbation of the tumour’s microenvironment increases the exposure of immunological epitopes and removes anti-inflammatory regulatory cells, permitting immune cell infiltration and improved anti-tumour immunity.6 Recent developments include the phase 1 clinical trial of histotripsy on nonresectable hepatic tumours (THERESA), which was successful7—all eight patients experienced no procedural complications two months after the procedure, and tissue was effectively targeted and destroyed in both primary and secondary tumours.

Warren A Campbell IV

The future of histotripsy is currently being developed in the lab, with a focus on improving the safety, efficacy, and versatility of the procedure. Utilisation of microbubbles and fluid-filled polymer capsules can make histotripsy safer by reducing the energy required for cavitation. Liposomes could also transport drug payloads (i.e. chemotherapies), where histotripsy initiates targeted release. Histotripsy may also permit the diffusion of larger nonpermeable biopharmaceuticals like heparin and insulin through skin via histotripsy of the stratum corneum, eliminating the need for regular injections. The debulking and tumour-targeting functions have already been proven in clinical trials, but these advancements will increase its synergistic effects with other oncological therapies.

Histotripsy is the most recent development of high-intensity focused ultrasound techniques, which have the added benefit of mechanical tissue destruction with increased precision and targeting that is less invasive than alternative techniques. Histotripsy may also have the added benefit of increasing tumour immunogenicity in metastatic disease. Preclinical models in multiple cancers have been effective, and the first human trial targeting hepatic tumours was safe and effective. The future of histotripsy includes a range of applications to treat patients increasingly safely and non-invasively.

References:

  1. Bader, KB, Vlaisavljevich, E & Maxwell, AD For whom the bubble grows: Physical principles of bubble nucleation and dynamics in histotripsy ultrasound therapy. Ultrasound Med. Biol. 45, 1056–1080 (2019).
  2. Nault, J-C, Sutter, O, Nahon, P, Ganne-Carrié, N & Séror, O Percutaneous treatment of hepatocellular carcinoma: State of the art and innovations. J. Hepatol. 68, 783–797 (2018).
  3. Wang, Y-N et al. Mechanical decellularisation of tissue volumes using boiling histotripsy. Phys. Med. Biol. 63, 235023 (2018).
  4. Wang, T-Y et al. Quantitative ultrasound backscatter for pulsed cavitational ultrasound therapy-histotripsy. IEEE Trans. Ultrason. Ferroelectr. Freq. Control 56, 995–1005 (2009).
  5. Izadifar, Z, Izadifar, Z, Chapman, D & Babyn, P An Introduction to High Intensity Focused Ultrasound: Systematic Review on Principles, Devices, and Clinical Applications. J. Clin. Med. 9, 460 (2020).
  6. Hendricks-Wenger, A, Hutchison, R, Vlaisavljevich, E & Allen, IC Immunological Effects of Histotripsy for Cancer Therapy. Front. Oncol. 11, 681629 (2021).
  7. Vidal-Jove, J et al. First-in-man histotripsy of hepatic tumours: The THERESA trial, a feasibility study. Int. J. Hyperthermia 39, 1115–1123 (2022).

Disclosures: The authors declared no relevant disclosures.


LEAVE A REPLY

Please enter your comment!
Please enter your name here