autologous orthogonal IL-2Rbeta-expressing anti-CD19 CAR T cells SYNCAR-001

A preparation of autologous T lymphocytes that have been genetically modified and transduced with a lentiviral vector expressing a chimeric antigen receptor (CAR) targeting the tumor-associated antigen (TAA) CD19 fused to the extracellular, transmembrane and intracellular signaling domains of the T-cell co-stimulatory receptor CD28 and the cytoplasmic signaling domain of the zeta chain of the TCR/CD3 complex (CD3-zeta) and expressing a mutated orthogonal (ortho) interleukin (IL)-2beta receptor (hoRbeta; hoRb), with potential immunostimulating and antineoplastic activities. Upon administration, autologous hoRb-expressing anti-CD19 CAR T-cells SYNCAR-001 target and bind to CD19-expressing tumor cells, thereby inducing selective toxicity in CD19-expressing tumor cells. CD19 antigen is a B-cell specific cell surface antigen expressed in all B-cell lineage malignancies. Stimulation of hoRb specifically by orthogonal (ortho) IL-2 STK-009 allows for IL-2 signaling specifically in SYNCAR-001 and leads to increased proliferation, persistence and anti-tumor activity of SYNCAR-001. This may lead to dose reduction of SYNCAR-001. hoRb does not respond to the native IL-2 ligand. As STK-009 does not cause IL-2-mediated signaling in other immune cells, systemic toxicity is limited.