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 Hubbard, Alexander D Borowsky, Katherine W. Ferrara

Research output: Contribution to journalArticle

2 Citations (Scopus)

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

Fingerprint

Immunotherapy
Breast Neoplasms
Neoplasms
Cross-Priming
Doxorubicin
Drug Therapy
Liposomes
Fever
Interferon Type I
Antigen Presentation
Adaptive Immunity
Neoplasm Antigens
Intravenous Injections
Copper
Cell Death
Cytokines
Antigens
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Kheirolomoom, A., Silvestrini, M. T., Ingham, E. S., Mahakian, L. M., Tam, S. M., Tumbale, S. K., ... 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

Combining activatable nanodelivery with immunotherapy in a murine breast cancer model. / Kheirolomoom, Azadeh; Silvestrini, Matthew T.; Ingham, Elizabeth S.; Mahakian, Lisa M.; Tam, Sarah M.; Tumbale, Spencer K.; Foiret, Josquin; Hubbard, Neil; Borowsky, Alexander D; Ferrara, Katherine W.

In: Journal of Controlled Release, Vol. 303, 10.06.2019, p. 42-54.

Research output: Contribution to journalArticle

Kheirolomoom, A, Silvestrini, MT, Ingham, ES, Mahakian, LM, Tam, SM, Tumbale, SK, Foiret, J, Hubbard, N, Borowsky, AD & Ferrara, KW 2019, 'Combining activatable nanodelivery with immunotherapy in a murine breast cancer model', Journal of Controlled Release, vol. 303, pp. 42-54. https://doi.org/10.1016/j.jconrel.2019.04.008
Kheirolomoom A, Silvestrini MT, Ingham ES, Mahakian LM, Tam SM, Tumbale SK et al. Combining activatable nanodelivery with immunotherapy in a murine breast cancer model. Journal of Controlled Release. 2019 Jun 10;303:42-54. https://doi.org/10.1016/j.jconrel.2019.04.008
Kheirolomoom, Azadeh ; Silvestrini, Matthew T. ; Ingham, Elizabeth S. ; Mahakian, Lisa M. ; Tam, Sarah M. ; Tumbale, Spencer K. ; Foiret, Josquin ; Hubbard, Neil ; Borowsky, Alexander D ; Ferrara, Katherine W. / Combining activatable nanodelivery with immunotherapy in a murine breast cancer model. In: Journal of Controlled Release. 2019 ; Vol. 303. pp. 42-54.
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