A new type of cancer therapy that engineers a patient’s own immune cells to attack tumours is being redesigned to make it safer, cheaper, and practical for routine NHS use. Current CAR T-cell therapy for B-cell cancers works well but causes severe side effects, including dangerous immune overreactions and permanent loss of healthy B-cells. Manufacturing the engineered cells is also slow, expensive, and difficult to scale. This project addresses both problems. The team has built a safer CAR19 design that includes a “suicide switch”—a protein tag that allows doctors to destroy the engineered cells with a common drug if toxicity becomes severe. They have also developed a faster, simpler 10-day manufacturing process using disposable bioreactors and a specially modified lentiviral vector that both activates and genetically modifies T-cells in one step. If successful, this approach could make CAR T-cell therapy deliverable in standard NHS haematology labs across the UK, rather than only in a handful of specialist centres. The researchers plan to test the therapy in two large phase I trials for acute and chronic B-cell malignancies, measuring safety, feasibility, and cost-effectiveness. Their longer-term goal is a viable national strategy for CAR19 within the NHS.
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Chimeric Antigen Receptors (CARs)1 are chimeric proteins generated by fusing the antigen-binding region of a monoclonal antibody (mAb) to intracellular T-cell signalling domains. They graft the specificity of a mAb onto the potent effector mechanisms of a T-cell. Large numbers of CAR T-cells can be generated by isolating and transducing a patient s peripheral blood T-cells with an integrating vector coding for the CAR. After infusion, these cells can home, extravasate and penetrate a solid core of tumour, proliferate8 and persist9. Recent clinical data described in neuroblastoma10 and more dramatically in CD19 CAR2–5 targeting for treatment of B-cell malignancies (CAR19) have shown unprecedented responses in patients with refractory disease. CAR therapy is already a disruptive force in the treatment of cancer and looks set to soon find routine application in salvage of refractory B-cell malignancy. Despite the promising clinical data, many challenges remain before CAR19 can be more widely adopted in the NHS, even for the narrow indication of refractory B-cell malignancy. Severe immediate and late toxicity have been evident which include cytokine storms, delayed macrophage activating syndromes, with CAR designs associated with better responses typically causing more toxicity11. Permanent depletion of the B-cell compartment can be poorly tolerated in some patients. Large-scale manufacturing of retroviral and lentiviral vectors remains largely an unsolved problem12. It is also unclear what the most cost-effective manufacturing model of bespoke CAR T-cell products for each patient will be. We have developed a CAR19 strategy which overcomes the above challenges with a view to wider deployment of CAR19 beyond experimental clinical studies. We have developed a CD19 CAR based on a different CD19 binder characterized at UCL. This CAR transmits a 41BB activation signal which appears to be the optimal format for B-cell malignancies. We believe this CAR is at least as potent as those tested in the US. With safety in mind, we have generated a sort-suicide gene termed RQR8. This is a small type-I membrane protein which contains two copies of the Rituximab binding epitopes from CD20 which allows selective destruction of CAR T-cells by administration of Rituximab. We also have addressed manufacturing problems: UCL has pioneered retroviral and lentiviral pseudotyping with the RD114 envelope. This envelope allows generation of stable, high-titer vectors particularly effective at transducing T-cells. Using RD114 pseudotyping, we have generated means of generating large amounts of virus and purifying it. In addition, we have developed a means of incorporating T-cell activation domains in the lentiviral capsid this allowing one reagent to both activate and transduce T-cells. These new technologies allowing us overcome the problem of large-scale vector manufacture and efficient T-cell transduction. Using this stimulating and transducing lentiviral vector, we have developed a simple 10-day process using disposable bioreactors to expand and transduce T-cells at scale sufficient for therapeutic application. The simplicity and relatively small amount of handling of this methodology should make it transferrable to most accredited haematopoietic stem cell processing labs present in all large centres in the UK, providing a cost-effective solution to CAR T-cell manufacture. We believe we can deliver a CAR19 programme which will be highly competitive both technically but particularly in terms of scalability and cost-effectiveness. Our immediate aim is to implement two large phase I studies in acute and chronic B-cell malignancies and show feasibility of our approach and safety of the therapeutic. We plan to demonstrate CAR therapy is feasible using typical NHS and UK infrastructure. We will determine cost-effectiveness of our programme. Our longer term vision is that we can provide a viable national strategy for CAR19 within the NHS, and a model
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