CAR-T therapy relies on removing T-cells from a patient and modifying them to attack cancer cells. Source: iStock

Juno Therapeutics has announced the main conclusions of their internal investigation into the deaths of five patients involved in the company’s CAR-T clinical trials last year, Science reports. They believe that a combination of inherent variation in the patients and product variability was behind the cerebral edema that killed five of the participants with leukaemia. The company hopes that this research will help to inform future trials and therapies to ensure better and safer treatments.

Last year, Juno Therapeutics was running a clinical trial known as ROCKET, which was attempting to use CAR-T therapy to treat patients with Acute Lymphoblastic Leukaemia (ALL). The trial was halted, however, when five of the patients involved in the trial died from fatal swelling in the brain, a condition called cerebral oedema. Since then, Juno has been working on an investigation to uncover exactly what caused these deaths and how it may be avoided in future.

On Friday, representatives from Juno which included the Chief Medical Officer, Mark Gilbert, MD, reported their findings at the AGM of the Society for Immunotherapy of Cancer in Maryland. The investigation revealed that several patients had suffered from severe neurologic toxicity during the trial, which has been seen in other CAR-T therapies, but that in some cases, this toxicity progressed to cerebral oedema. Other CAR-T therapies haven’t demonstrated similar results and so the team tried to find out why.

Autopsies of two of the deceased patients uncovered a complete breakdown of the blood-brain barrier, which would account for cerebral swelling. However, they also unexpectedly found that the surrounding brain tissue was free of the engineered T-cells used in CAR-T therapy.

While Juno have kept some of the details of their investigation private, Dr. Gilbert did say that they had concluded the main cause behind the unexpected deaths was a combination of factors. For one, the patients involved had significant natural variability in their immune systems and for a treatment like CAR-T, which is highly personalised, this can lead to complications. Dr. Gilbert also commented that the treatments the patients received were inconsistent, in particular with regards to the quantities of T-cell subtypes present in each dose.

Another factor may have been the rate at which the modified T-cells multiplied after reinsertion. In most cases, cell proliferation takes place roughly 12 to 14 days after the dose is administered; in the patients who died, the proliferation was noted 6 to 8 days after treatment and this likely increased the risk of neurotoxicity.

Juno hope to use the knowledge they have gained from this investigation to improve their future CAR-T therapies, such as their second therapy which is currently in Phase I trials and is aimed at patients with non-Hodgkin lymphoma. If successful, it would be the third CAR-T therapy to make it to market after Novartis’ Kymriah for children with ALL and Gilead Science’s Yescarta for patients with non-Hodgkin lymphoma.