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Oncoimmunology. 2018 Jan 9;7(3):e1395997. doi: 10.1080/2162402X.2017.1395997. eCollection 2018.

Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines.

Author information

1
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
2
current address: Preclinical Pharmacology, Incyte Corporation, Wilmington, DE, USA.
3
Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
4
Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
5
University of Pittsburgh Cancer Institute, and Departments of Surgery and Immunology, University of Pittsburgh, Pittsburgh, PA, USA.

Abstract

T cell trafficking into tumors depends on a "match" between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor "mismatch", with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti-tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti-tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy.

KEYWORDS:

CAR T cells; CXCL11; adoptive T cell transfer; cancer vaccines; chemokines; immunotherapy; lung cancer; mesothelioma; vaccinia virus

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