Histotripsy Tumor Ablation Research is Published in the Journal for ImmunoTherapy of Cancer

January 22, 2020 / Portfolio News
HistoSonics Cancer Immunotherapy

On January 15, 2020, HistoSonics’ research on non-thermal histotripsy tumor ablation was published in the Journal for ImmunoTherapy of Cancer (JITC), the premier cancer immunotherapy journal at BMC and the official journal of the Society for Immunotherapy of Cancer (SITC). An excerpt from the report can be found below.

Read the Full Report here.

Original Source: Qu S, Worlikar T, Felsted AE, et al. Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy. Journal for ImmunoTherapy of Cancer 2020;8:e000200.doi:10.1136/jitc-2019-000200

The Results

  1. Histotripsy promotes local intratumoral innate and adaptive immune responses.
  2. Histotripsy mediates stronger intratumoral CD8+ T cell infiltration than other modalities of tumor-directed therapy
  3. Non-thermal histotripsy is capable of releasing immunogenic tumor neoantigens
  4. Histotripsy is associated with regional and systemic tumor-specific CD8+ T cell responses
  5. Histotripsy is associated with the induction of abscopal intratumoral CD8+ T cell responses
  6. Histotripsy inhibits the development of distant metastases
  7. Histotripsy is associated with the induction of systemic inflammatory changes and local release of HMGB1
  8. Histotripsy augments the efficacy of checkpoint inhibition immunotherapy

Background

Recent advances in checkpoint inhibition immunotherapy have renewed investigative interest into the possibility that tumor-directed therapies like thermal ablation and radiation, could stimulate tumor-directed immune responses.

Although immunostimulatory effects have been observed with thermal ablation and radiation, the magnitude of these effects has not yet proven capable of consistently augmenting the effect of immunotherapy. One potential immunostimulatory limitation of tumor-directed therapies may be their inability to induce sufficient tumorous release of immunogenic or inflammatory subcellular components, such as neoantigens or damage-associated molecular patterns (DAMPs) like high mobility group box protein 1 (HMGB1) that are capable of triggering strong tumor-directed adaptive immune responses.

Histotripsy is a novel modality of non-invasive tumor ablation that uses overlapping high-pressure ultrasound pulses to disrupt cellular architecture. At their point of convergence, focused ultrasound waves create precise regions of extreme pressure changes. Histotripsy uses microsecond-length ultrasound pulses to mechanically homogenize tissues through acoustic cavitation; by separating these pulses by milliseconds off-time or longer, heat generation is avoided. When applied to tumors, histotripsy reduces tumor tissue to a liquefied acellular homogenate that is gradually reabsorbed. 11–18

By lysing target cells through a strictly mechanical mechanism that avoids the denaturing effects of heat or ionizing radiation, we hypothesized that histotripsy could promote inflammatory and immunostimulatory effects not possible with other modalities of tumor-directed therapy like thermal ablation or radiation.

For the purposes of this report, a murine model of subcutaneous tumor ablation was used to demonstrate that histotripsy is uniquely capable of promoting local, regional and systemic antitumor adaptive immune responses that can significantly augment the efficacy of checkpoint inhibition immunotherapy.

Conclusions

Our observations suggest that histotripsy is capable of stimulating local, regional and systemic antitumor immune responses that, when further amplified by checkpoint inhibition, may be sufficient to make a clinical impact against previously immunoresistant cancers. If so, the immunomodulatory impact of histotripsy may be key to expanding the impact and promise of cancer immunotherapy.

Related Article: HistoSonics Leads The Observer’s 2020 List of Innovative Healthcare Companies

References

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Authors

Author Affiliations

1 Surgery, University of Michigan, Ann Arbor, Michigan, USA
2 Department of Hepatobiliary Surgery, Xijing Hospital, Xian, Shaanxi, China
3 Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA
4 Surgery, VA Ann Arbor Healthcare System, Ann Arbor, Michigan, USA
5 Surgery, Ohio State University Medical Center, Columbus, Ohio, USA

Contributors

SQ, AEF, AG, MVB, ALP, AAK, HG, JD, and MT performed in vivo tumor inoculations and treatments and in vitro assays. TW and RH performed in vivo histotripsy treatments. HH performed HMGB1 assays. SQ, TW, AEF, AG, RH, ALP, AAK, AT, ZX and CSC performed data analysis and interpretation. SQ, TW, AEF, AT, ZX and CSC wrote the manuscript. SQ, TW, AEF, AG, MVB, RH, ALP, AAK, MT, HH, AT, ZX and CSC performed manuscript review, editing, and approval.

Funding

This work was funded by VA Merit Review 1I01BX001619-05 (to CSC), NIH Grant R01-CA211217 (to ZX), University of Michigan Forbes Institute for
Discovery (to CSC and ZX), HistoSonics-Michigan Corporate Relations Network Grant AWD006745 (to CSC), NIH Grant T32-CA009672 (to AEF), and NIH Grant T32-CA090217 (to MVB). This work was supported by NIH Grant P30-CA04659229 to the University of Michigan Rogel Cancer Center. The content is solely the responsibility of the authors and does not represent the views of the Department of Veterans Affairs or the US Government or the National Institutes of Health.

Competing interests

None declared

Patient consent for publication

None required

Ethics approval

The murine experiments were prospectively reviewed and approved by the University of Michigan and VA Ann Arbor Healthcare Animal Care and Use Committees.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

Data are available upon reasonable request

Open access

This is an open-access article distributed in accordance with the
Creative Commons Attribution Non-Commercial (CC BY-NC
4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http:// creativecommons. org/ licenses/ by- nc/4.0/.

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