Selective B Cell Depletion Upon Intravenous Infusion of Replication-Incompetent Anti-CD19 CAR Lentivirus
This week we profile a recent publication in Molecular Therapy Methods & Clinical Development from first author Dr. Craig Rive (pictured, far left) in the lab of Dr. Robert Holt (center, back) at Canada’s Michael Smith Genome Sciences Centre.
Can you provide a brief overview of your lab’s current research focus?
Our lab’s overall focus involves understanding and genetically manipulating the human immune system to help fight a range of cancers. We recently initiated CD19 CAR-T cell project that has involved the design, manufacturing and delivery CD19 CAR-T cell therapy to leukemia and lymphoma patients here in BC. However, we are also looking for ways to improve CD19 CAR-T therapy by developing a safe and effective treatment method that does not rely on isolating and manipulating patient’s T cells in the lab, which is logistically difficult and very expensive. By delivering the CAR gene directly, by intravenous infusion of the gene transfer vector, rather than the pre-modified cells, it becomes an “off-the shelf” treatment, rather than a personalized treatment, which has the potential to dramatically reduce the costs of treatment but also serve to increase overall feasibility and accessibility.
What is the significance of the findings in this publication?
When we first tested (in laboratory mice) if it’s possible to generate CD19 CAR-T cells in vivo, and saw success, no one else had had tried it. Since then, others have also successfully generated CD19 CAR-T cells in vivo using a variety of gene transfer systems. In our current publication, we show that using the conventional gene transfer vector (lentivirus) it’s feasible to generate CD19 CAR-T cells in vivo. With an eye towards improve safety and efficacy, we feel it is now appropriate to press ahead with the further characterization and pre-clinical assessment needed to move toward testing the safety and efficacy of this approach in a clinical trial. There is a lot more work needed in this regard, to ensure we would be able to selectively target T cells in the body.
What are the next steps for this research?
Now we have shown that we can generate CD19 CAR-T cells in vivo in a mouse model system, the next steps include repeating the in vivo transduction of T cells in tumour bearing mice, to how effectively this approach can eliminate cancer cells. While we hypothesize the presence of tumour should not affect the transduction of T cells, and that T cells generated in vivo should be as effective as those produced in the lab, we still need to test this hypothesis. After this, the goal is to improve the efficiency and safety of our viral gene delivery system so that we can either directly target T cells for transduction and/or reduce expression of the CD19 CAR-T transgene to T cells only.
If you’d like to mention your funding sources, please list them.
This research was supported by the British Columbia Cancer Foundation, the Leon Judah Blackmore Foundation, Canadian Institutes of Health Research (CIHR) and the BioCanRx network.