Universität zu Köln

Kunert, A., Chmielewski, M., Wijers, R., Berrevoets, C., Abken, H. and Debets, R. (2018). Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors. OncoImmunology, 7 (1). PHILADELPHIA: TAYLOR & FRANCIS INC. ISSN 2162-402X

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Abstract

Adoptive therapy with engineered T cells shows promising results in treating patients with malignant disease, but is challenged by incomplete responses and tumor recurrences. Here, we aimed to direct the tumor microenvironment in favor of a successful immune response by local secretion of interleukin (IL-) 12 and IL-18 by sadministered T cells. To this end, we engineered T cells with a melanoma-specific T cell receptor (TCR) and murine IL-12 and/or IL-18 under the control of a nuclear-factor of activated T-cell (NFAT)-sensitive promoter. These T cells produced IL-12 or IL-18, and consequently enhanced levels of IFN, following exposure to antigen-positive but not negative tumor cells. Adoptive transfer of T cells with a TCR and inducible (i)IL-12 to melanoma-bearing mice resulted in severe, edema-like toxicity that was accompanied by enhanced levels of IFN and TNF in blood, and reduced numbers of peripheral TCR transgene-positive T cells. In contrast, transfer of T cells expressing a TCR and iIL-18 was without side effects, enhanced the presence of therapeutic CD8(+) T cells within tumors, reduced tumor burden and prolonged survival. Notably, treatment with TCR+iIL-12 but not iIL-18 T cells resulted in enhanced intra-tumoral accumulation of macrophages, which was accompanied by a decreased frequency of therapeutic T cells, in particular of the CD8 subset. In addition, when administered to mice, iIL-18 but not iIL-12 demonstrated a favorable profile of T cell co-stimulatory and inhibitory receptors. In conclusion, we observed that treatment with T cells engineered with a TCR and iIL18 T cells is safe and able to skew the tumor microenvironment in favor of an improved anti-tumor T cell response.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kunert, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chmielewski, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wijers, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Berrevoets, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Abken, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Debets, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-204213
DOI:	10.1080/2162402X.2017.1378842
Journal or Publication Title:	OncoImmunology
Volume:	7
Number:	1
Date:	2018
Publisher:	TAYLOR & FRANCIS INC
Place of Publication:	PHILADELPHIA
ISSN:	2162-402X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTERFERON-GAMMA PRODUCTION; CHIMERIC ANTIGEN RECEPTORS; METASTATIC MELANOMA; CANCER-PATIENTS; INTERLEUKIN-12; LYMPHOCYTES; IL-12; LYMPHOMA; IMMUNOTHERAPY; RECURRENCE Multiple languages Oncology; Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20421