T-Cells Redirected Against CD70 for the Immunotherapy of Hematological Malignancies.

BACKGROUND: CD70 is a tumor necrosis family member that is expressed on a broad spectrum of hematological malignancies including multiple myeloma, non-Hodgkin’s lymphomas and Hodgkin’s disease. In contrast to other already established immunotherapy targets such as CD19, CD20, or CD52, which are widely expressed in the hematopoietic system, CD70 expression is restricted to a subset of activated B and T cells, reducing potential ‘collateral damage’ when targeted by immunotherapy. Preclinical studies in animal models using monoclonal antibodies have validated CD70 as an immunotherapeutic target for malignancies and the aim of this study was to generate CD70-specific T cells for adoptive immunotherapy approaches.

METHODS and RESULTS: To create CD70-specific T cells we constructed a CD70-specific chimeric antigen receptor (CD70-CAR) consisting of domains derived from the CD70 receptor (CD27) and the T-cell receptor CD3-ζ chain. CD70-specific T cells were generated by transducing CD3/CD28-activated T cells with a SFG retroviral vector encoding the CD70-CAR. Cell surface expression of CD70-CARs was confirmed by FACS analysis on CD4- as well as CD8-positive T cells. CD70-specific T cells from healthy donors proliferated and produced IFN-γ as well as IL-2 in contrast to mock transduced T cells after coculture with CD70-positive myeloma cells (U266 and ARH-77) and lymphoblastoid cell lines. In cytotoxicity assays, CD70-specific T cells killed CD70-positive myeloma cell lines and lymphoblastoid cell lines where as activated lymphocytes that express CD70 at low levels and CD70-negatvie targets were not killed.

CONCLUSION: We have successfully constructed a CD70-CAR and demonstrate that CD70-specific T cells selectively recognize and kill malignant cells that express CD70 at high levels. Murine xenograft studies are in progress to confirm these findings in vivo. Adoptive immunotherapy with CD70-specific T cells may represent a promising immunotherapeutic approach for CD70-positive hematological malignancies.