GDA-601: CRISPR knockout of CD38 and expression of anti CD38 CAR to enhance primary NK anti-tumor activity against Multiple myeloma

Multiple myeloma (MM) is a hematological disorder characterized by the expansion of malignant plasma cells in the bone marrow. MM cells commonly express CD38 transmembrane glycoprotein that acts as a receptor. Daratumumab (Dara), a human monoclonal antibody targeting CD38, applies anti-MM activity via several Fc-dependent mechanisms and significantly improves the outcome of MM patients. However, the response to Dara is mostly transient. CD38 expression on NK cells represents a barrier to developing CD38 CAR-NK cell therapy. To overcome anticipated fratricide, we applied CRISPR/Cas9 genome editing to eliminate CD38 protein expression on Gamida-cell NAM-NKs.

To obviate the need for Dara and control the killing and fratricide potential, we constructed an anti CD38 NK-CAR that will be delivered to the CD38 KO NAM-NKs as an mRNA post-harvest.

Our results suggest that the CD38 CRISPR Knock-Out (KO) is very efficient, characterized by significant elimination of CD38 expression and negligible “off-target” activity. As expected, CD38 KO NK cells were resistant to fratricide. In addition, to improve cancer therapy and prevent the need for an anti-CD38 antibody, such as Dara, we constructed and expressed anti-CD38 CAR on the NK CD38 KO cells. In in vitro functional experiments, we demonstrate that the combination of CD38 KO and anti-CD38 CAR expression leads to a better killing and higher potency activity against MM cell lines, in comparison to control NK cells without the genetically engineered manipulation. Taken together, GDA-601 displays superior antitumoral responses against multiple myeloma cells and represents a promising adoptive cell therapeutic strategy against multiple myeloma