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Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols
Matthew T. Silvestrini, … , Alexander D. Borowsky, Katherine W. Ferrara
Matthew T. Silvestrini, … , Alexander D. Borowsky, Katherine W. Ferrara
Published March 23, 2017
Citation Information: JCI Insight. 2017;2(6):e90521. https://doi.org/10.1172/jci.insight.90521.
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Research Article Oncology Therapeutics

Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols

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Abstract

Focal therapies play an important role in the treatment of cancers where palliation is desired, local control is needed, or surgical resection is not feasible. Pairing immunotherapy with such focal treatments is particularly attractive; however, there is emerging evidence that focal therapy can have a positive or negative impact on the efficacy of immunotherapy. Thermal ablation is an appealing modality to pair with such protocols, as tumors can be rapidly debulked (cell death occurring within minutes to hours), tumor antigens can be released locally, and treatment can be conducted and repeated without the concerns of radiation-based therapies. In a syngeneic model of epithelial cancer, we found that 7 days of immunotherapy (TLR9 agonist and checkpoint blockade), prior to thermal ablation, reduced macrophages and myeloid-derived suppressor cells and enhanced IFN-γ–producing CD8+ T cells, the M1 macrophage fraction, and PD-L1 expression on CD45+ cells. Continued treatment with immunotherapy alone or with immunotherapy combined with ablation (primed ablation) then resulted in a complete response in 80% of treated mice at day 90, and primed ablation expanded CD8+ T cells as compared with all control groups. When the tumor burden was increased by implantation of 3 orthotopic tumors, successive primed ablation of 2 discrete lesions resulted in survival of 60% of treated mice as compared with 25% of mice treated with immunotherapy alone. Alternatively, when immunotherapy was begun immediately after thermal ablation, the abscopal effect was diminished and none of the mice within the cohort exhibited a complete response. In summary, we found that immunotherapy begun before ablation can be curative and can enhance efficacy in the presence of a high tumor burden. Two mechanisms have potential to impact the efficacy of immunotherapy when begun immediately after thermal ablation: mechanical changes in the tumor microenvironment and inflammatory-mediated changes in immune phenotype.

Authors

Matthew T. Silvestrini, Elizabeth S. Ingham, Lisa M. Mahakian, Azadeh Kheirolomoom, Yu Liu, Brett Z. Fite, Sarah M. Tam, Samantha T. Tucci, Katherine D. Watson, Andrew W. Wong, Arta M. Monjazeb, Neil E. Hubbard, William J. Murphy, Alexander D. Borowsky, Katherine W. Ferrara

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Figure 1

MRgFUS ablation promotes local antitumor immune response.

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MRgFUS ablation promotes local antitumor immune response.
(A) Regimen of...
(A) Regimen of thermal ablation in mice orthotopically transplanted with neu deletion line (NDL) tumor biopsies in the fourth and ninth mammary fat pad. (B and C) Magnetic resonance–guided focused ultrasound (MRgFUS) ablation protocol and temperature mapping for thermal ablation in vivo (white color indicates minimum threshold of 70°C). (B) T1w images of localized region to be ablated (red dotted circle). (C) MR thermometry image following ablation protocol (red arrow indicates heated region). (D–F) NDL tumor growth following MRgFUS ablation (n = 7) compared with no-treatment (NT) control NDL tumor growth (n = 34 total, 8 representative growth curves shown for this individual study). Mice per group examined in 3 separate experiments. (D) Thermally ablated tumors exhibited a transient suppression in growth compared with (E) contralateral and (F) NT control tumors. (G–I) The entire fourth and ninth mammary fat pad (tumor and embedded lymph node) was harvested at day 28, and immune cells were quantified by flow cytometry (n = 4 per group). Effect of therapy on (G) IFN-γ CD4+ T cells, (H) CD8+ T cells, and (I) Tregs in the treated and contralateral tumors. For box-and-whiskers plots, the whiskers represent the minimum and maximum values, the box boundaries represent the 25th and 75th percentiles, and the middle line is the median value. (J) High mobility group box 1 (HMGB1) protein release in vitro quantified via ELISA. Treatment with doxorubicin (Dox) at 37°C represents a positive control. Each dot represents a sample. Data are mean ± SEM of 3 measurements. (K–M) H&E staining performed at day 31 confirmed that, compared with (K) control tumors (n = 3), viable tumor was reduced in (L) treated tumors (n = 3), where residual viable tumor tissue (red arrows) existed outside the path of the ultrasound beam. Thermal ablation did not reduce viable (M) contralateral tumor tissue (n = 3). *P < 0.05, **P < 0.01, ****P < 0.0001, †P < 0.05 compared with 37°C group, ‡P < 0.01 compared with 37°C + Dox group. Scale bar: 3 mm. Statistics for G–I were determined by ANOVA followed by Fisher’s LSD without multiple comparisons correction, and those for J were determined by ANOVA followed by Tukey multiple comparison correction.

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