Developing CD70-Targeted CAR-T Cells for the Treatment of Hematological and Solid Malignancies

The immune checkpoint molecule cluster of differentiation 70 (CD70), is implicated in tumor proliferation and immune evasion, as its aberrant expression has been observed in multiple hematologic malignancies and solid tumors, including acute myeloid leukemia (AML) and renal cell carcinoma (RCC). Expression of CD70 in normal tissues is restricted to activated T, B, natural killer lymphocytes, and mature dendritic cells. This restricted expression pattern of CD70 in normal tissues makes it an attractive target for cancer therapy.

Chimeric antigen receptor (CAR) T cell therapy offers an exciting new therapeutics modality and has gained regulatory approvals to treat hematologic malignancies. Here, we generated a CD70-directed CAR-T structure that contained a nanoantibody for CD70 targeting, the CD8 derived transmembrane domain as a linker to the intracellular activation signal, 41BB as costimulatory domain, and the CD3-zeta as the activation signal. The anti-CD70 nanobody was found to bind human CD70 with high affinity and more importantly, although CD70 is expressed in activated T cells, the nanobody directed CAR T cells could be produced and manufactured successfully at clinical scale without apparent loss of cell expansion, indicating that our CAR could mask CD70 in CAR-T cells and prevent fratricide. Furthermore, the CD70 CAR T cells displayed potent anti-tumor activities, as evident by in vitro killing against CD70 expressed cell lines, such as Molm-13, an AML cell line, or ACHN, a RCC cell line; and by in vivo tumor inhibition and clearance in immunodeficient xenograft mouse model. Together, our data support the further development of CD70-targeted CAR-T cells for the treatment of hematological and solid malignancies.

No relevant conflicts of interest to declare.