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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 4

Comparison of coincident TA-immunotherapy (ablation + CpG + αPD-1) with immunotherapy alone (CpG + αPD-1).

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Comparison of coincident TA-immunotherapy (ablation + CpG + αPD-1) with ...
CpG+αPD-1 reduces macrophages and myeloid-derived suppressor cells (MDSCs) in contralateral tumors and increases PD-L1 expression in tumor-infiltrating leukocytes. Coincident thermoablative immunotherapy (TA-immunotherapy) increases macrophages in treated tumors. (A–E) Animals were treated as described in Figure 3A with thermal ablation, CpG (100 μg per injection), and αPD-1 (200 μg per injection). Treatment cohorts were NT control (n = 8), CpG + αPD-1 (n = 8), and ablation + CpG + αPD-1 (n = 8). (A and B) The frequency of (A) macrophages and (B) MDSCs in the treated and contralateral tumors following treatment. The fourth and ninth mammary fat pads (tumor and the embedded node) were harvested at day 35 and immunocytes were quantified via flow cytometry. (C–E) Expression of PD-1 and PD-L1 in treated and contralateral tumors. Tumors were harvested at day 28, and immunocytes were quantified via flow cytometry. (C) The amount of PD-1 expressed on CD4+ T cells, the (D) expression of PD-L1 on tumor/stromal cells (CD45–), and (E) the expression of PD-L1 on CD45+ leukocytes in 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. Statistics in A–E were determined by ANOVA followed by Fisher’s LSD test without multiple comparisons correction. *P < 0.05, **P < 0.01, ***P < 0.001, ‡P < 0.05 compared with all groups.

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