Dataset Information

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

ABSTRACT:

Purpose

Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors.

Experimental design

We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival.

Results

Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4⁺Foxp3⁺, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4⁺, CD8α⁺, and CD8α⁺CD11c⁺ cells, CD11c⁺ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P < 0.0001). This combination treatment significantly also induces CD4⁺CD44^+hiCD62L^+low and CD8α⁺CD44^+hiCD62L^+low population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment.

Conclusions

Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.

SUBMITTER: Eranki A

PROVIDER: S-EPMC9009723 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

Eranki Avinash A Srinivasan Priya P Ries Mario M Kim AeRang A Lazarski Christopher A CA Rossi Christopher T CT Khokhlova Tatiana D TD Wilson Emmanuel E Knoblach Susan M SM Sharma Karun V KV Wood Bradford J BJ Moonen Chrit C Sandler Anthony D AD Kim Peter C W PCW

Clinical cancer research : an official journal of the American Association for Cancer Research 20191015 5

<h4>Purpose</h4>Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors.<h4>Experimental design</h4>We treated <2% of tumor volume in previously unresponsive, large, refractory murine neurobla ...[more]

PMID: 31615935

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Project description:ObjectivesDeep infiltrating endometriosis (DIE) of the rectosigmoid is associated with painful symptoms. When medical treatment is ineffective, surgical resection remains the standard treatment, despite significant risk of adverse events. High-intensity focused ultrasound (HIFU) is a minimally invasive ablative procedure. Focal One® is a transrectal HIFU (TR-HIFU) device used in prostate cancer treatment. The primary objective of this study was to confirm the feasibility of treatment with TR-HIFU in patients presenting with posterior DIE with rectosigmoid involvement. We also assessed its safety and clinical efficacy in this context.MethodsThis was a non-controlled, prospective, Phase-I clinical trial in a French University Hospital which is a multidisciplinary center for management of endometriosis. Included were patients older than 25 years, without plans to conceive within 6 months, who presented with a single lesion of posterior DIE, with rectosigmoid invasion, after failure of hormonal therapy. All lesions were assessed preoperatively using transvaginal sonography and magnetic resonance imaging. Patients completed questionnaires on gynecological and intestinal symptoms (similar to a visual analog scale (VAS)), and on quality of life (Medical Outcomes Study 36-item short-form survey (SF-36) and, for the second half of patients recruited, symptom scoring system for constipation (KESS), female sexual function index (FSFI) and endometriosis health profile short-version score (EHP-5)), before, and at 1, 3 and 6 months after, TR-HIFU treatment with a Focal One real-time ultrasound-guided HIFU device.ResultsTwenty-three consecutive patients were included in the study between September 2015 and October 2019. All 23 lesions were visualized, giving a detection rate of 100%. Twenty lesions were treated ('feasibility rate', 87.0%): in 13 the whole lesion was treated and in seven the lesion was treated partially. The mean duration of the TR-HIFU procedure was 55.6 min. We observed a significant improvement in VAS score at 6 months, with differences relative to preoperative scores as follows, for: dysmenorrhea (-3.6, P = 0.004), dyspareunia (-2.4, P = 0.006), diarrhea (-3.0, P = 0.006), constipation (-3.0, P = 0.002), dyschezia (-3.2, P = 0.003), false urge to defecate (-3.3, P = 0.007), posterior pelvic pain (-3.8, P = 0.002) and asthenia (-3.8, P = 0.002). There was also a significant improvement in the SF-36 score, with an increase at 6 months relative to the preoperative score in both the physical component summary (+ 9.3%, P = 0.002) and mental component summary (+ 10.9%, P = 0.017). No major complications occurred during or after any procedure.ConclusionsTR-HIFU therapy for posterior DIE is feasible. If its efficacy and safety are confirmed, it could be a minimally invasive alternative to surgery for the treatment of rectosigmoid endometriosis. © 2019 Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Dataset Information

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

Purpose

Experimental design

Results

Conclusions

Publications

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

Similar Datasets

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