In an effort to improve T cell trafficking to the tumor, Moon et al. aimed to increase levels of CXCL11 (a chemokine that attracts effector T cells via the CXCR3 receptor) in the murine tumor microenvironment. After failing to demonstrate improved tumor control by delivering CXCL11 as part of a mesothelin-targeted CAR vector, the team used a modified oncolytic vaccinia virus as a CXCL11 vector (VV.CXCL11) which improved T cell infiltration, tumor control, and overall survival only when combined with an E7 cancer vaccine or with antigen-specific CAR T cells.

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.

Author Info: (1) Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Medicine, Perelman School of Medicine at

Author Info: (1) Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. current address: Preclinical Pharmacology, Incyte Corporation, Wilmington, DE, USA. (3) Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (4) Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Biomedical Sciences, School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, PA, USA. (6) University of Pittsburgh Cancer Institute, and Departments of Surgery and Immunology, University of Pittsburgh, Pittsburgh, PA, USA. (7) Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

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