Background CAR T cell therapy is remarkably successful in patients with hematological malignancies, in some cases inducing durable remissions. However, it remains ineffective in solid tumors, in part due to poor T cell infiltration into the tumor mass. Determinants of successful T cell infiltration to the tumor site remain to be defined. In contrast, tumors actively attract T regulatory (Treg) cells for immune suppression through the C-C chemokine receptor 8 (CCR8) - CCL1 axis. As this axis is functional across cancer entities, we postulated that CCR8 could also be used to target tumor-ablating T cells to the tumor site.
Material and methods Murine and human CCR8 have been cloned in a retroviral expression vector. CCR8 can be expressed in murine and human T cells upon transduction. A chimeric antigen receptor (CAR) targeting the murine epithelial cell adhesion molecule (EpCAM) was used for syngeneic pancreatic tumor models and a CAR targeting human mesothelin was used for a xenograft pancreatic tumor model.Mechanistically, we use flow cytometry and multi-photon intra-vital microscopy to interrogate infiltration of CCR8-transduced CAR T cells.
Results Here we show that genetically engineering CAR T cells to express CCR8 improves their migration into solid tumors and allows rejection of tumors that are otherwise resistant to CAR T cell therapy. We demonstrate the capacity of these enhanced CAR T cells to stunt solid tumor growth and improve survival in both murine syngeneic and human xenograft tumor models.
Conclusion Our results demonstrate the viability of using CCR8 to confer Tregcell trafficking-properties in CAR T cells to enable their effectiveness in solid tumors. This receptor may be combined with other promising strategies to improve the efficacy of cellular approaches.
Disclosure Information B. L. Cadilha: None. K. Dorman: None. D. Huynh: None. T. Lorenzini: None. M. Vänttinen: None. M. -R. Benmebarek: None. S. Stoiber: None. J. Suárez-Gosálvez: None. S. Endres: None. S. Kobold: None.
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