Combining activatable nanodelivery with immunotherapy in a murine breast cancer model

• Published in: Journal of controlled release Vol. 303; pp. 42 - 54
• Main Authors: Kheirolomoom, Azadeh, Silvestrini, Matthew T, Ingham, Elizabeth S, Mahakian, Lisa M, Tam, Sarah M, Tumbale, Spencer K, Foiret, Josquin, Hubbard, Neil E, Borowsky, Alexander D, Ferrara, Katherine W
• Format: Journal Article
• Language: English
• Published: Netherlands 10.06.2019
• Subjects: αPD-1; Immunotherapy; Breast cancer; CpG; Doxorubicin; Ultrasound; Temperature-sensitive liposome
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2019.04.008

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.