Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1.
Animals
Antibodies, Monoclonal
/ administration & dosage
Antibodies, Monoclonal, Humanized
/ administration & dosage
Antineoplastic Agents
/ administration & dosage
B7-H1 Antigen
/ administration & dosage
CD40 Antigens
/ administration & dosage
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Combined Modality Therapy
/ methods
Drug Implants
Female
Freeze Drying
Immunotherapy
/ adverse effects
Injections, Intralesional
/ methods
Injections, Intraperitoneal
Liver Neoplasms
/ secondary
Lung Neoplasms
/ secondary
Mice
Mice, Inbred BALB C
Progression-Free Survival
Radiation Dose Hypofractionation
Random Allocation
Response Evaluation Criteria in Solid Tumors
Theranostic Nanomedicine
/ methods
Treatment Outcome
Triple Negative Breast Neoplasms
/ immunology
Tumor Burden
Journal
International journal of radiation oncology, biology, physics
ISSN: 1879-355X
Titre abrégé: Int J Radiat Oncol Biol Phys
Pays: United States
ID NLM: 7603616
Informations de publication
Date de publication:
01 06 2021
01 06 2021
Historique:
received:
24
02
2020
revised:
29
05
2020
accepted:
29
07
2020
pubmed:
10
8
2020
medline:
27
8
2021
entrez:
10
8
2020
Statut:
ppublish
Résumé
Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden. Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.
Identifiants
pubmed: 32768562
pii: S0360-3016(20)33745-7
doi: 10.1016/j.ijrobp.2020.07.2326
pmc: PMC8547413
mid: NIHMS1627321
pii:
doi:
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Monoclonal, Humanized
0
Antineoplastic Agents
0
B7-H1 Antigen
0
CD40 Antigens
0
Drug Implants
0
atezolizumab
52CMI0WC3Y
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
492-506Subventions
Organisme : NCI NIH HHS
ID : R01 CA127483
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204191
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA208703
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM127558
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
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