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Int J Cancer. 2017 Oct 1;141(7):1458-1468. doi: 10.1002/ijc.30839. Epub 2017 Jun 29.

Adenoviral production of interleukin-2 at the tumor site removes the need for systemic postconditioning in adoptive cell therapy.

Author information

1
TILT Biotherapeutics Ltd, Helsinki, Finland.
2
Department of Pathology, Faculty of Medicine, Cancer Gene Therapy Group, University of Helsinki, Finland.
3
Pathology Unit, Finnish Food Safety Authority (EVIRA), Helsinki, Finland.
4
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.
5
Department of Obstetrics and Gynecology, Helsinki University Hospital, Finland.
6
Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland.

Abstract

Systemic high dose interleukin-2 (IL-2) postconditioning has long been utilized in boosting the efficacy of T cells in adoptive cell therapy (ACT) of solid tumors. The resulting severe off-target toxicity of these regimens renders local production at the tumor an attractive concept with possible safety gains. We evaluated the efficacy and safety of intratumorally administered IL-2-coding adenoviruses in combination with tumor-infiltrating lymphocyte therapy in syngeneic Syrian hamsters bearing HapT1 pancreatic tumors and with T cell receptor transgenic ACT in B16.OVA melanoma bearing C57BL/6 mice. The models are complementary: hamsters are semi-permissive for human oncolytic adenovirus, whereas detailed immunological analyses are possible in mice. In both models, local production of IL-2 successfully replaced the need for systemic recombinant IL-2 (rIL-2) administration and increased the efficacy of the cell therapy. Furthermore, vectored delivery of IL-2 significantly enhanced the infiltration of CD8+ T cells, M1-like macrophages, and B-cells while systemic rIL-2 increased CD25 + FoxP3+ T cells at the tumor. In contrast with vectored delivery, histopathological analysis of systemic rIL-2-treated animals revealed significant changes in lungs, livers, hearts, spleens, and kidneys. In summary, local IL-2 production results in efficacy and safety gains in the context of ACT. These preclinical assessments provide the rationale for ongoing clinical translation.

KEYWORDS:

T cell therapy; adoptive cell therapy; immunotherapy; interleukin-2; oncolytic adenovirus

PMID:
28614908
DOI:
10.1002/ijc.30839
[Indexed for MEDLINE]
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