Articles In the 2 0 years that I have worked in the pharmaceutical industry, I have never felt so optimistic that we can make a big difference to the outlook for cancer patients. The current revolution in immunotherapy goes well beyond targeted drug therapy: by utilising the power of the immune system, we have the opportunity to develop multiple approaches to cancer therapy that could not only dramatically extend the lives of some cancer patients, but also deliver this promise to a much broader range of patients and tumour types, and for longer periods of time. Back in 1989, I had no inkling that my early forays into understanding the immune system would lead me down the path of cancer treatment. As you sit in one of the many teaching sessions throughout medical school, just remind yourself that what you learn today may end up being far more valuable than you ever envisaged.
Image by Karim Chraihi
By Alexander Gray Chief Medical Officer, IDEA Pharma
CAR Immunotherapy:
Driving Research from Bench to Bedside
T
he history of cell and gene therapy is not one without its peaks and pitfalls. This novel type of therapy promised to treat and cure almost any disease by inserting a corrective gene into the cells, with an important caveat: the molecular pathogenesis of the disease had to be properly understood. This year marks the eighteenth anniversary of Jesse Gelsinger’s death, the first directly attributed to gene therapy treatment. Gelsinger had ornithine transcarbamylase (OTC) deficiency, a metabolic disorder that prevents the body from breaking down and eliminating the build-up of ammonia. The gene delivery vehicle — a recombinant adenoviral vector — provoked an immune reaction, causing brain damage and organ failure. Gelsinger died a few days later in the autumn of 1999. His death rocked the gene therapy community and resulted in increased regulatory control in gene therapy trials. Since the 90s, the field of cell and gene therapy has progressed by leaps and bounds with the refinement of chimeric antigen receptor (CAR) T-cell therapy. The aim of CAR T-cell therapy is to harness the body’s immune T-cells, which normally target and kill infected cells, and genetically modify them to recognise and target tumour antigens. We can achieve this by endowing the T-cell with a CAR, which is a synthetic protein that combines the antigen-binding domain of
an antibody with the T-cell signalling machinery. In a nutshell, the patient’s immune cells are harvested, genetically modified to express a a CAR in a purpose-built clean-room, and then expanded to billions of cells before cryopreservation and subsequent re-infusion into the patient at the bedside. Over the last five years, CAR T-cell therapy has made waves in the scientific and medical community. Clinical trials in the US and worldwide have shown great promise, particularly in the treatment of B-cell malignancies in patients who have become refractory to both first-line treatment and salvage therapy, causing remissions in a number of patients. To date, over 1500 patients have been enrolled and treated in CAR T-cell trials worldwide. The UCL CAR Immunotherapy Programme was launched under the direction of Dr Martin Pule, senior lecturer in haematology at UCL. This started with a Bloodwise-funded study, called COBALT, targeting CD19 in diffuse large B-cell lymphoma. At the initial development stage, we designed and created a whole range of candidate CARs in order to provide and deliver the best possible therapeutic living drug. Each candidate had different binding domains from antibodies targeting CD19 and different T-cell activation domains. Our CAR candidates were engineered from donated peripheral blood with target-positive tumour cells expressing CD19 and target-negative tumour cells