Novartis entered into a $90 MM deal with Oxford Biomedica for use of its lentiviral vectors with its CAR (chimeric antigen receptor) modified T-cell product, CTL019, being developed with researchers at UPENN.
CTL019 is a product based on patients autologous T-cells engineered to express receptors (antibody constructs) that recognize CD19 on the surface of B-cells. In clinical studies in highly refractor patients with acute lymphoblastic leukemia who have failed multiple prior chemotherapeutic regimens and bone marrow transplants, 90% of patients have been induced into complete remissions. These results, reported October 16, 20104 in the New England Journal of Medicine, are truly remarkable.
A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab.
Why lentiviral vectors. Simple – in order for the therapy to broadly applicable, repeatable and efficient methods for transducing the T-cells are required. And, lentiviral vectors, because they are retroviruses, like HIV, are very efficient at transfecting T-cells. For example, look at the diagram below for gene therapy of combined immunodeficiency syndrome in which the lentiviral vector is being used to express cytokine receptors in T-cells.
This construct is easily adapted for the delivery of the chimeric antigen receptor consists of an intracellular T-cell receptor CD3-zeta chain signaling domain that induces T-cell activation, a costimulatory 4-1BB domain that enhances T-cell mediated responses and anti-CD19 antibody fragments that bind to CD19.