TY - JOUR
T1 - Nanoparticles that reshape the tumor milieu create a therapeutic window for effective t-cell therapy in solid malignancies
AU - Zhang, Fan
AU - Stephan, Sirkka B.
AU - Ene, Chibawanye I.
AU - Smith, Tyrel T.
AU - Holland, Eric C.
AU - Stephan, Matthias T.
N1 - Funding Information:
This work was supported by the Fred Hutchinson Cancer Research Center's Immunotherapy Initiative, with funds provided by the Bezos Family Foundation (M.T. Stephan), the NCI (RO1CA195718; M.T. Stephan and E.C. Holland), and the Immunotherapy Integrated Research Center (IIRC) at Fred Hutchinson Cancer ResearchCenter (Collaborative Grant Accelerator; M.T.Stephan and E.C. Holland).
Publisher Copyright:
©2018 AACR.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here, we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove protumor cell populations and simultaneously stimulate antitumor effector cells. We administered repeated infusions of lipid nanoparticles coated with the tumor-targeting peptide iRGD and loaded with a combination of a PI3K inhibitor to inhibit immune-suppressive tumor cells and an a-GalCer agonist of therapeutic T cells to synergistically sway the tumor microenvironment of solid tumors from suppressive to stimulatory. This treatment created a therapeutic window of 2 weeks, enabling tumor-specific CAR-T cells to home to the lesion, undergo robust expansion, and trigger tumor regression. CAR-T cells administered outside this therapeutic window had no curative effect. The lipid nanoparticles we used are easy to manufacture in substantial amounts, and we demonstrate that repeated infusions of them are safe. Our technology may therefore provide a practical and low-cost strategy to potentiate many cancer immunotherapies used to treat solid tumors, including T-cell therapy, vaccines, and BITE platforms. Significance: A new nanotechnology approach can promote T-cell therapy for solid tumors.
AB - A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here, we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove protumor cell populations and simultaneously stimulate antitumor effector cells. We administered repeated infusions of lipid nanoparticles coated with the tumor-targeting peptide iRGD and loaded with a combination of a PI3K inhibitor to inhibit immune-suppressive tumor cells and an a-GalCer agonist of therapeutic T cells to synergistically sway the tumor microenvironment of solid tumors from suppressive to stimulatory. This treatment created a therapeutic window of 2 weeks, enabling tumor-specific CAR-T cells to home to the lesion, undergo robust expansion, and trigger tumor regression. CAR-T cells administered outside this therapeutic window had no curative effect. The lipid nanoparticles we used are easy to manufacture in substantial amounts, and we demonstrate that repeated infusions of them are safe. Our technology may therefore provide a practical and low-cost strategy to potentiate many cancer immunotherapies used to treat solid tumors, including T-cell therapy, vaccines, and BITE platforms. Significance: A new nanotechnology approach can promote T-cell therapy for solid tumors.
UR - http://www.scopus.com/inward/record.url?scp=85049610120&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049610120&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-0306
DO - 10.1158/0008-5472.CAN-18-0306
M3 - Article
C2 - 29760047
AN - SCOPUS:85049610120
SN - 0008-5472
VL - 78
SP - 3718
EP - 3730
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -