ORLANDO – A cellular therapy called FT596 is active against B-cell malignancies and, when combined with rituximab, can be more effective than traditional chimeric antigen receptor (CAR) T cells, preclinical research findings suggest.
FT596 is a universal, anti-CD19 CAR natural killer (NK) cell therapy derived from a master induced pluripotent stem cell (iPSC) line.
FT596 reduced tumor growth in mouse models of leukemia and lymphoma. When combined with rituximab, FT596 was able to overcome CD19 antigen escape.
, of Fate Therapeutics in San Diego, presented these results at the annual meeting of the American Society of Hematology.
Dr. Goodridge explained that FT596 begins with a source material, such as a fibroblast, that is reprogrammed into an iPSC progenitor cell. That cell is sorted and expanded into a renewable, homogeneous, pluripotent master iPSC line. The iPSCs are differentiated into CD34 cells, which are differentiated into NK cells. The iPSC-derived NK cells are then modified with the following:
- An anti-CD19 CAR that is optimized for NK-cell biology and contains an NKG2D transmembrane domain, a 2B4 costimulatory domain, and a CD3-zeta signaling domain.
- An interleukin-15 receptor fusion that promotes cell survival and reduces the need for cytokine support.
- A high-affinity 158V, noncleavable CD16 Fc receptor that enhances antibody-dependent cellular cytotoxicity when FT596 is combined with a monoclonal antibody such as rituximab.
Dr. Goodridge presented results with FT596, both alone and in combination with rituximab, in vitro and in vivo.
When compared with no treatment, three doses of FT596 monotherapy reduced tumor growth in a mouse model of leukemia (Nalm6). FT596 plus rituximab reduced tumor growth in a mouse model of lymphoma (Raji), when compared with no treatment or rituximab alone.
Three doses of FT596 proved more effective than a single dose of CD19 CAR T-cell therapy in a mouse model of lymphoma (Raji). FT596 both reduced tumor growth and prolonged survival in the mice.
Lastly, in vitro experiments in Raji cells showed that FT596 plus rituximab can produce deeper responses than primary CAR-T cells, and the combination can prevent antigen escape.
Dr. Goodridge said these results support the phase 1 study of FT596, given as monotherapy or in combination with rituximab or obinutuzumab, in patients with relapsed/refractory B-cell lymphomas or chronic lymphocytic leukemia.
Dr. Goodridge is employed by Fate Therapeutics, the company developing FT596.
SOURCE: Goodridge JP et al. ASH 2019. .