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 language | English (US) |
|---|---|
| Pages (from-to) | 42-54 |
| Number of pages | 13 |
| Journal | Journal of Controlled Release |
| Volume | 303 |
| DOIs | |
| State | Published - Jun 10 2019 |
Fingerprint
Keywords
- Breast cancer
- CpG
- Doxorubicin
- Immunotherapy
- Temperature-sensitive liposome
- Ultrasound
- αPD-1
ASJC Scopus subject areas
- Pharmaceutical Science
Cite this
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 journal › Article
}
TY - JOUR
T1 - Combining activatable nanodelivery with immunotherapy in a murine breast cancer model
AU - Kheirolomoom, Azadeh
AU - Silvestrini, Matthew T.
AU - Ingham, Elizabeth S.
AU - Mahakian, Lisa M.
AU - Tam, Sarah M.
AU - Tumbale, Spencer K.
AU - Foiret, Josquin
AU - Hubbard, Neil
AU - Borowsky, Alexander D
AU - Ferrara, Katherine W.
PY - 2019/6/10
Y1 - 2019/6/10
N2 - 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.
AB - 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.
KW - Breast cancer
KW - CpG
KW - Doxorubicin
KW - Immunotherapy
KW - Temperature-sensitive liposome
KW - Ultrasound
KW - αPD-1
UR - http://www.scopus.com/inward/record.url?scp=85064316275&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064316275&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2019.04.008
DO - 10.1016/j.jconrel.2019.04.008
M3 - Article
C2 - 30978432
AN - SCOPUS:85064316275
VL - 303
SP - 42
EP - 54
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -