Combining activatable nanodelivery with immunotherapy in a murine breast cancer model

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

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

A successful chemotherapy-immunotherapy solid-tumor protocol should accomplish the following goals: debulk large tumors, release tumor antigen for cross-presentation and cross-priming, release cancer-suppressive cytokines and enhance anti-tumor immune cell populations. Thermally-activated drug delivery particles have the potential to synergize with immunotherapeutics to accomplish these goals; activation can release chemotherapy within bulky solid tumors and can enhance response when combined with immunotherapy. We set out to determine whether a single protocol, combining locally-activated chemotherapy and agonist immunotherapy, could accomplish these goals and yield a potentially translational therapy. For effective delivery of free doxorubicin to tumors with minimal toxicity, we stabilized doxorubicin with copper in temperature-sensitive liposomes that rapidly release free drug in the vasculature of cancer lesions upon exposure to ultrasound-mediated hyperthermia. We found that in vitro exposure of tumor cells to hyperthermia and doxorubicin resulted in immunogenic cell death and the local release of type I interferons across murine cancer cell lines. Following intravenous injection, local activation of the liposomes within a single tumor released doxorubicin and enhanced cross-presentation of a model antigen at distant tumor sites. While a variety of protocols achieved a complete response in >50% of treated mice, the complete response rate was greatest (90%) when 1 week of immunotherapy priming preceded a single activatable chemotherapeutic administration. While repeated chemotherapeutic delivery reduced local viable tumor, the complete response rate and a subset of tumor immune cells were also reduced. Taken together, the results suggest that activatable chemotherapy can enhance adjuvant immunotherapy; however, in a murine model the systemic adaptive immune response was greatest with a single administration of chemotherapy.

Original languageEnglish (US)
Pages (from-to)42-54
Number of pages13
JournalJournal of Controlled Release
Volume303
DOIs
StatePublished - Jun 10 2019

Keywords

  • Breast cancer
  • CpG
  • Doxorubicin
  • Immunotherapy
  • Temperature-sensitive liposome
  • Ultrasound
  • αPD-1

ASJC Scopus subject areas

  • Pharmaceutical Science

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  • Cite this

    Kheirolomoom, A., Silvestrini, M. T., Ingham, E. S., Mahakian, L. M., Tam, S. M., Tumbale, S. K., Foiret, J., Hubbard, N. E., Borowsky, A. D., & Ferrara, K. W. (2019). Combining activatable nanodelivery with immunotherapy in a murine breast cancer model. Journal of Controlled Release, 303, 42-54. https://doi.org/10.1016/j.jconrel.2019.04.008