CD70-targeted iPSC-derived CAR-NK cells display potent function against tumors and alloreactive T cells

Area of Science:

• Immunotherapy
• Cancer Research
• Stem Cell Biology

Background:

• Autologous chimeric antigen receptor (CAR)-T cell therapy faces challenges in manufacturing time, cost, and cancer type specificity.
• There is a need for off-the-shelf, universally applicable immune cell therapies.

Purpose of the Study:

• To develop an allogeneic, off-the-shelf immune cell therapy using engineered induced pluripotent stem cell-derived natural killer (iNK) cells.
• To enhance the anti-tumor efficacy and persistence of CAR-NK cells by targeting CD70 and incorporating additional genetic modifications.

Main Methods:

• Generation of CD70-targeted CAR-NK (70CAR-iNK) cells from induced pluripotent stem cells (iPSCs).
• Multi-gene editing of 70CAR-iNK cells, including CD70 gene knockout, introduction of high-affinity non-cleavable CD16 (hnCD16), and an interleukin-15 receptor α/IL-15 fusion protein (IL15RF).
• Assessment of 70CAR-iNK cell cytotoxicity against various tumor cell lines and in vivo efficacy in xenograft models.

Main Results:

• Multi-gene-edited 70CAR-iNK cells displayed robust cytotoxicity against a broad spectrum of tumors.
• In vivo studies confirmed potent anti-tumor activity against lymphoma and renal cancer xenografts.
• 70CAR-iNK cells effectively eliminated recipient alloreactive T cells expressing CD70, enhancing iNK cell survival and persistence.

Conclusions:

• CD70-targeted, multi-gene-edited iNK cells represent a promising universal immune cell therapy platform.
• The ability to target tumors and eliminate alloreactive T cells positions 70CAR-iNK cells as a next-generation therapeutic candidate.