Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System

Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-n...

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Veröffentlicht in:Cell reports (Cambridge) Jg. 23; H. 7; S. 2130 - 2141
Hauptverfasser: Avanzi, Mauro P., Yeku, Oladapo, Li, Xinghuo, Wijewarnasuriya, Dinali P., van Leeuwen, Dayenne G., Cheung, Kenneth, Park, Hyebin, Purdon, Terence J., Daniyan, Anthony F., Spitzer, Matthew H., Brentjens, Renier J.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 15.05.2018
Schlagworte:
adoptive transfer
Animals
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
armored CAR
Autocrine Communication - drug effects
B-ALL
B-Lymphocytes - drug effects
CAR T cell
Cell Proliferation - drug effects
Cell Survival - drug effects
chimeric antigen receptor
Disease Models, Animal
Humans
IL-18
Immune System - drug effects
Immune System - metabolism
Immunotherapy
Immunotherapy, Adoptive
interleukin-18
Interleukin-18 - metabolism
Mice, Inbred C57BL
Mice, SCID
MUC16
Neoplasms - drug therapy
Neoplasms - immunology
Neoplasms - pathology
ovarian cancer
Signal Transduction - drug effects
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
Tumor Microenvironment - drug effects
Xenograft Model Antitumor Assays
armored CAR
B-ALL
MUC16
interleukin-18
ovarian cancer
IL-18
chimeric antigen receptor
adoptive transfer
CAR T cell
ISSN:2211-1247, 2211-1247
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Zusammenfassung:Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin’s lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL-18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18-secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18-secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy. [Display omitted] •IL-18-secreting CAR T cells enhance anti-tumor efficacy via IL-18 autocrine stimulation•IL-18-secreting CAR T cells favorably alter EL4 tumor microenvironment•IL-18-secreting CAR T cells enhance the anti-tumor response of endogenous T cells•IL-18-secreting CAR T cells are efficacious in syngeneic models without preconditioning Avanzi et al. generate CAR T cells that secrete IL-18 and show improved activity in syngeneic hematologic and solid tumor models without prior preconditioning. They further show enhanced recruitment and anti-tumor activity of endogenous T cells.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
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These authors contributed equally
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.04.051