Sleeping beauty-mediated CAR T cell therapy offers hope for cancer patients

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A Phase 1 clinical trial demonstrates the potential of sleeping beauty (SB)-mediated CAR T cell therapy in combination with hematopoietic stem cell transplantation (HSCT) for the treatment of advanced non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL).

T cells genetically modified with lentivirus or retrovirus, to express chimeric antigen receptors (CAR) have been shown to improve outcomes for CD19-expressing B cell malignancies. However, recombinant viral vector–based immunotherapy faces several pitfalls including cost issues, complexity and cytokine release syndrome. The present study investigated the potential of sleeping beauty (SB) transposon/transposase system to genetically modify T cells, to express a CD19-specific CAR. The SB system uses a synthetic DNA transposon for nonviral somatic gene transfer. An advantage of the SB system is that plasmids can be produced for use in compliance with cGMP for lesser cost as compared to clinical-grade recombinant viral vectors.

In the present study published in The Journal of Clinical Investigation, the research team led by Prof. Laurence Cooper at the University of Texas MD Anderson Cancer Center evaluated the potential of using SB-mediated CD19-specific CAR T cells as adjuvant therapy following autologous and allogeneic HSCT in 26 patients with advanced NHL and ALL. To produce CD19 CAR T cells, peripheral blood mononuclear cells were electroporated with SB transposon and transposase plasmids encoding CD19. The electroporated cells were expanded ex vivo on γ-irradiated activating and propagating cells (AaPCs) and cytokines to enable selective growth of T cells stably encoding the CD19-specific CAR.

Results showed that SB-mediated genetic transposition and stimulation resulted in significantly high ex vivo expansion of genetically modified T cells, with 84% CAR expression. Autologous and allogeneic HSCT resulted in 100% and 63% overall survival rates, respectively. No toxicities were associated with the use of SB transposase system. The CAR T cells persisted for an average of 201 days for autologous recipients and 51 days for allogeneic recipients.

Thus, the study showed that CD19-specific CAR T cells generated with SB and AaPC platforms were safe, and may provide additional strategy for cancer control after HSCT administration. These results support further clinical development of this non-viral gene therapy approach. The study also highlights the safety and feasibility of using both autologous and allogeneic CAR T cells produced in compliance with cGMP for phase 1/2 trials.

Source: Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. Kebriaei P et al., The Journal of Clinical Investigation August 2016. DOI