Combining activatable nanodelivery with immunotherapy in a murine breast cancer model

Kheirolomoom, Azadeh; Silvestrini, Matthew T.; Ingham, Elizabeth S.; Mahakian, Lisa M.; Tam, Sarah; Tumbale, Spencer K.; Foiret, Josquin; Hubbard, Neil E.; Borowsky, Alexander D.; Ferrara, Katherine W.

doi:10.1016/j.jconrel.2019.04.008

Cited by 34 publications

(27 citation statements)

References 49 publications

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“…In vitro secretion of IFN-β reached 150 pg/10 6 cells for the remaining viable tumor cells, a 150-fold increase compared to no-US or no-plasmid controls and a 50-fold increase compared to treatment with TMBs and US (without IFN-β). This result exceeds values of fourfold to fivefold improvement reported for ablative, radiotherapy, and chemotherapeutic treatments in previous in vitro studies (60,63,64). Second, by incorporating a checkpoint inhibitor, we were able to enhance T cell recruitment as a result of sonoporation.…”

Section: Discussioncontrasting

confidence: 53%

Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites

Ilovitsh

Feng

Foiret

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Robust cytotoxic T cell infiltration has proven to be difficult to achieve in solid tumors. We set out to develop a flexible protocol to efficiently transfect tumor and stromal cells to produce immune-activating cytokines, and thus enhance T cell infiltration while debulking tumor mass. By combining ultrasound with tumor-targeted microbubbles, membrane pores are created and facilitate a controllable and local transfection. Here, we applied a substantially lower transmission frequency (250 kHz) than applied previously. The resulting microbubble oscillation was significantly enhanced, reaching an effective expansion ratio of 35 for a peak negative pressure of 500 kPa in vitro. Combining low-frequency ultrasound with tumor-targeted microbubbles and a DNA plasmid construct, 20% of tumor cells remained viable, and ∼20% of these remaining cells were transfected with a reporter gene both in vitro and in vivo. The majority of cells transfected in vivo were mucin 1+/CD45−tumor cells. Tumor and stromal cells were then transfected with plasmid DNA encoding IFN-β, producing 150 pg/106cells in vitro, a 150-fold increase compared to no-ultrasound or no-plasmid controls and a 50-fold increase compared to treatment with targeted microbubbles and ultrasound (without IFN-β). This enhancement in secretion exceeds previously reported fourfold to fivefold increases with other in vitro treatments. Combined with intraperitoneal administration of checkpoint inhibition, a single application of IFN-β plasmid transfection reduced tumor growth in vivo and recruited efficacious immune cells at both the local and distant tumor sites.

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Section: Discussioncontrasting

confidence: 53%

Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites

Ilovitsh

Feng

Foiret

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“… 23 Further, intratumoral CpG treatment supports the immunogenicity of hyperthermia-treated BrCa. 30 The argument for immune priming is based on the assertion that (1) inflammatory insults induced by FUS may result in rebound immune suppression by MDSCs and M2 polarization or (2) the degree of myeloid cell activation achieved by the release of DAMPS with thermal ablation-induced sterile inflammation is insufficient. Our data support the latter argument, as modest intratumoral DC activation was observed with ablative FUS alone, with negligible impact on MDSC.…”

Section: Discussionmentioning

confidence: 99%

Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity

Sheybani

Witter

Thim

et al. 2020

J Immunother Cancer

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BackgroundTriple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs).MethodsWe applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1−/− mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival.ResultsThe immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1.ConclusionThermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.Trial registration numbersNCT03237572 and NCT04116320.

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“…Amplification of systemic antigen cross-presentation, type 1 interferon release, and CD169+ myeloid cell recruitment were observed in the setting of ablation combined with immunotherapy - suggestive that this paradigm was capable of enriching for a unique class of antigen-presenting cells that cross-prime independent of DCs. In an adaptation of this combinatorial approach in murine breast cancer, the combination of single dose thermally activatable doxorubicin-loaded liposomes with FUS hyperthermia and an adjuvant agonistic immunotherapy priming protocol (anti-PD1 + CpG) elicited treated and distant tumor eradication, as well as significant survival benefit 45. In this study, complete response rate was greatest in mice when immunotherapy priming was conducted prior to administering a single dose of chemotherapy.…”

Section: New Pre-clinical Investigations Combining Fus With Checkpoinmentioning

confidence: 86%

“…Publications emerging in the field have called immunological priming to attention as a means towards achieving effective FUS immunotherapy. Notably, these studies arrived at priming as an important consideration when coincident immunotherapy protocols did not yield similar success 43-45 (Figure 5). However, other studies have seen efficacy in the context of checkpoint inhibition similarly targeting the PD-1/PD-L1 axis without the need for priming 46.…”

Section: New Pre-clinical Investigations Combining Fus With Checkpoinmentioning

confidence: 99%

Perspectives on Recent Progress in Focused Ultrasound Immunotherapy

Sheybani

Price

2019

Theranostics

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Immunotherapy holds tremendous promise as a strategy for eradicating solid tumors. However, poor T cell infiltration and persistence within most solid tumor microenvironments, as well as mechanisms of adaptive resistance, continue to severely limit the accessibility of most immunotherapies to a broad patient population. This limitation perpetuates the demand for allied therapeutic strategies. Among such strategies is focused ultrasound (FUS), a non-invasive, non-ionizing technique for precisely targeted acoustic energy deposition into tissues. FUS has gained remarkable attention over recent years as a modality for elicitation of immune mechanisms in cancer and other pathologies. In 2017, we published a comprehensive review paper detailing existing evidence for immune modulation and therapy with FUS, as well as impending challenges and opportunities of consideration for the field. Over the last two years, a multitude of clinical trials have come online to explore safety, feasibility, and efficacy of FUS for cancers of the brain and periphery - including the first clinical trial to combine FUS with immunotherapy. Moreover, the last two years have seen a surge in FUS immunotherapy presentations at therapeutic ultrasound scientific meetings. Given the burst of activity in this field, we submit that an update on FUS immunotherapy progress is timely. In this review, we offer an updated overview and perspectives on scientific and clinical development in the FUS immunotherapy domain.

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Combining activatable nanodelivery with immunotherapy in a murine breast cancer model

Cited by 34 publications

References 49 publications

Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites

Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites

Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity

Perspectives on Recent Progress in Focused Ultrasound Immunotherapy

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