Pulsed focused ultrasound can improve the anti-cancer effects of immune checkpoint inhibitors in murine pancreatic cancer

Abstract

Pulsed high-intensity focused ultrasound (pHIFU) uses acoustic pressure to physically disrupt tumours. The aim of this study was to investigate whether pHIFU can be used in combination with immune checkpoint inhibitors (ICIs) to enhance survival of tumour-bearing animals. Murine orthotopic pancreatic KPC tumours were exposed both to a grid of pHIFU lesions (peak negative pressure = 17 MPa, frequency = 1.5 MHz, duty cycle = 1%, 1 pulse s −1 , duration = 25 s) and to anti-CTLA-4/anti-PD-1 antibodies. Acoustic cavitation was detected using a weakly focused passive sensor. Tumour dimensions were measured with B-mode ultrasound before treatment and with callipers post-mortem. Immune cell subtypes were quantified with immunohistochemistry and flow cytometry. pHIFU treatment of pancreatic tumours resulted in detectable acoustic cavitation and increased infiltration of CD8 + T cells in the tumours of pHIFU and pHIFU + ICI-treated subjects compared with sham-exposed subjects. Survival of subjects treated with pHIFU + ICI was extended relative to both control untreated subjects and those treated with either pHIFU or ICI alone. Subjects treated with pHIFU + ICI had increased levels of CD8 + IFNγ + T cells, increased ratios of CD8 + IFNγ + to CD3 + CD4 + FoxP3 + and CD11b + Ly6G + cells, and decreased CD11c high cells in their tumours compared with controls. These results provide evidence that pHIFU combined with ICI may have potential for use in pancreatic cancer therapy.

Boosting the Immune Response – Combining the Local and Immune Therapy for Prostate Cancer Treatment

“…Activation of anti-tumor immunity promoted by HIFU can be partially explained by tumor debris "left-over" antigens immunogenicity, which was demonstrated by Zhang et al in the murine hepatocellular carcinoma model [143]. Similar investigations have been conducted with other malignancies, such as melanoma, neuroblastoma, or pancreatic cancer [144][145][146][147][148][149]. Wu et al researched tumor debris immunogenic properties in 23 patients with breast cancer.…”

Latest Advances in the Use of Therapeutic Focused Ultrasound in the Treatment of Pancreatic Cancer

“…The purpose of this review is to detail the most important advances in ultrasound-induced immunity with a particular focus on the field of pancreatic cancer research. Both "thermal" and "mechanical" focused ultrasound can initiate immune responses in tumours by releasing tumour-associated antigens that lead to T cell-specific responses [108], increased tumour infiltrating lymphocytes (TIL) [109] and antigen-presenting cells (APC) [110] in the tumour microenvironment, activation of dendritic cells (DC) [111], change in the immune contexture of tumours [112], induction of the abscopal effect [108] and reversal of T cell anergy and tolerance [113].…”

“…Focused ultrasound could enhance the effects of immunotherapy in pancreatic cancer by destroying cancer cells, releasing tumour-specific antigens, DAMPS, and inducing ICD, thus attracting TIL, activating APC, including DC, and increasing the permeability of pancreatic tumour stroma thus allowing more immune-therapeutics to access the tumours (Table 3). Increased T cytotoxic cells, IFNγ + T cytotoxic cells and the ratio of these cells to T regulatory and MDSC in the tumours [112] The first clinical study to report the immunological effects of HIFU in the pancreas was published in 2002. Increased natural killer cell activity and increases in the abundance of TIL were seen after "thermal" HIFU treatment.…”

“…This improvement was associated with an increase in T cytotoxic , IFNγ + T cytotoxic cells, and the ratio of these cells to T regulatory and MDSC in the tumours of the animals treated with pHIFU and ICI compared to the control animals. These results suggested that treatment of pancreatic tumours with pHIFU can enhance ICI anti-cancer therapy by changing the immune contexture of tumours (parameters: f = 1.5 MHz, P-= 17 MPa, prf = 1 Hz, d.c. = 1%, pulse duration = 10 ms) [112].…”

Pancreatic Ductal Adenocarcinoma: Current and Emerging Therapeutic Uses of Focused Ultrasound

“…More anecdotally, two case studies reported abscopal effects following thermal ablation [ 111 , 112 ]. Preclinical data regarding immune effects in animal models of pancreatic cancer have recently been published [ 100 , 101 , 113 , 114 ]. The interested reader can refer to the detailed comprehensive review of those studies recently provided by Mouratidis and ter Haar [ 115 ].…”