Back to Search
Start Over
Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma.
- Source :
-
Nature communications [Nat Commun] 2021 Jan 19; Vol. 12 (1), pp. 444. Date of Electronic Publication: 2021 Jan 19. - Publication Year :
- 2021
-
Abstract
- Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer, for which effective therapies are urgently needed. Chimeric antigen receptor (CAR)-based immunotherapy represents a promising therapeutic approach, but it is often impeded by highly immunosuppressive tumor microenvironments (TME). Here, in an immunocompetent, orthotopic GBM mouse model, we show that CAR-T cells targeting tumor-specific epidermal growth factor receptor variant III (EGFRvIII) alone fail to control fully established tumors but, when combined with a single, locally delivered dose of IL-12, achieve durable anti-tumor responses. IL-12 not only boosts cytotoxicity of CAR-T cells, but also reshapes the TME, driving increased infiltration of proinflammatory CD4 <superscript>+</superscript> T cells, decreased numbers of regulatory T cells (Treg), and activation of the myeloid compartment. Importantly, the immunotherapy-enabling benefits of IL-12 are achieved with minimal systemic effects. Our findings thus show that local delivery of IL-12 may be an effective adjuvant for CAR-T cell therapy for GBM.
- Subjects :
- Animals
Brain diagnostic imaging
Brain immunology
Brain pathology
Brain Neoplasms diagnostic imaging
Brain Neoplasms immunology
Brain Neoplasms pathology
Cell Line, Tumor transplantation
Disease Models, Animal
ErbB Receptors immunology
Female
Glioblastoma diagnostic imaging
Glioblastoma immunology
Glioblastoma pathology
Humans
Immunoconjugates immunology
Immunoglobulin Fc Fragments administration & dosage
Immunoglobulin Fc Fragments immunology
Injections, Intralesional methods
Interleukin-12 immunology
Magnetic Resonance Imaging, Interventional
Mice
Receptors, Chimeric Antigen immunology
Single-Chain Antibodies administration & dosage
Single-Chain Antibodies immunology
T-Lymphocytes, Regulatory immunology
Tumor Microenvironment immunology
Brain Neoplasms therapy
Glioblastoma therapy
Immunoconjugates administration & dosage
Immunotherapy, Adoptive methods
Interleukin-12 administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 12
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33469002
- Full Text :
- https://doi.org/10.1038/s41467-020-20599-x