There’s nothing like getting a new CAR, in fact, it just might save your life. Results from a study at the American Society of Hematology meeting in San Francisco earlier this week showed that 36 of 39 paediatric patients with acute lymphoblastic leukaemia (ALL) went into complete remission after receiving genetically modified T-cells; the modification was with Novartis’ CTL019, a chimeric antigen receptor – a CAR.

In brief, a CAR is a custom version of the antigen-finding receptors that decorate the outer surfaces of the immune system’s killer T-cells; it is the part that identifies, binds to, and kills invading pathogens, or, with modification, tumour cells.  

The modification in this case allows for parking the CAR at a receptor known as CD-19, which is expressed on tumour cells in ALL and other haematologic malignancies.

“The external targeting domain is provided by a piece of an antibody,” said Stephan Grupp of the Children’s Hospital of Philadelphia, who reported the results of the study mentioned above. “In theory, anything that you can raise a monoclonal antibody against, you could use to target a CAR.”

To create a CAR, you first collect T-cells from the patient. These cells are then transfected with a viral vector that contains the genetic instructions for building the CAR, thereby allowing for the expression of the CAR protein on the surface of the T-cell.

This tweaked T-cell population is expanded in vitro and then infused back into the patient. Dr Grupp noted that to date, more than 130 people have been treated with CTL019.

92% in full remission

In the present study, 39 paediatric patients with relapsed or refractory ALL – a patient population for which there are few treatment options – received doses on the order of 10⁸ CAR T-cells/kg. Shortly after treatment, 92% of these difficult-to-treat patients were in full remission from their disease, and the overall response rate was 88%.

As to be expected in this gravely-ill population, there were relapses over time. In this study there were ten patients that relapsed. Of these, five were still CD-19 positive but were some of the sickest patients at study entry; the remaining  five patients had a loss of the CD-19 target, a phenomenon known as ‘antigen escape’.

Of note, the duration of treatment response observed suggests great promise for this novel therapeutic approach. “The median follow-up here is six months,” said Dr Grupp, pointing out that some patients were beyond one year post-treatment. “Our first patient treated is still doing well at 31 months.”

Persistence of the CAR cells in the body is a key point. “These cells can stick around for many months in patients, doing their thing,” Dr Grupp said. In fact, two-thirds of patients retain their T-cells for six months or more. “This is a key point in terms of maintaining remission in these patients.”

While CTL019 was well tolerated overall, there exists a potentially life-threatening side effect called cytokine release syndrome – and this is true for all CAR constructs. If caught in time, however, there is an effective treatment for this condition, the anti-IL-6 cytokine-targeting drug Actemra (tocilizumab) from Roche.

While this novel approach to treating cancer is still in its early stages the interest from the pharmaceutical industry has been enormous. Dr Grupp’s group is working closely with Novartis and Pfizer recently formed a CAR partnership with France’s Cellectis - there are CAR T programmes in place (or soon will be) at all major cancer centres.