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Neeson P.,Hematology and Immunology Translational Research Laboratory | Neeson P.,University of Melbourne | Shin A.,Hematology and Immunology Translational Research Laboratory | Tainton K.M.,Hematology and Immunology Translational Research Laboratory | And 18 more authors.
Gene Therapy | Year: 2010

The anti-tumor efficacy of adoptively transferred T cells requires their in vivo persistence and memory polarization. It is unknown if human chimeric antigen receptor (CAR)-expressing T cells can also undergo memory polarization. We examined the functional status of CAR CD8 T cells, re-directed to Lewis Y antigen (LeY-T), throughout a period of ex vivo expansion. Immediately before culture CD8 T cells comprised a mixture of phenotypes including naive (CD45RA /CCR7 /CD27 /CD28 /perforin), central memory (CM, CD45RA /CCR7 lo /CD27 /CD28 /perforin lo), effector memory (EM, CD45RA /CCR7 /CD27 /CD28 /perforin mod) and effector (Eff, CD45RA /CCR7 /CD27 /CD28 /perforin hi) cells. After transduction and expansion culture of peripheral blood mononuclear cells from normal donors or multiple myeloma patients, CD8 LeY-T cells polarized to EM- and CM-like phenotype. CD8 LeY-T cells differed from starting CD8 CM and EM T cells in that CD27, but not CD28, was downregulated. In addition, CD8 LeY-T cells expressed high levels of perforin, similar to starting CD8 Eff. CD8 LeY-T cells also showed hallmarks of both memory and Eff function, underwent homeostatic proliferation in response to interleukin (IL)-15, and showed interferon (IFN)-γ production and cytotoxicity in response to Le-Y antigen on OVCAR-3 (human ovarian adenocarcinoma) cells. This study confirms CD8 LeY-T cells have a CM- and EM-like phenotype and heterogeneous function consistent with potential to persist in vivo after adoptive transfer.

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