Making CAR-T Therapy Safer With Old RA Drugs
Personalised CAR-T treatments for blood cancer first hit the market last year, with Novartis’ Kymriah in August and Gilead’s Yescarta in October, and in so doing revolutionised the way we approach cancer treatments. The technique, which involves manipulating a patient’s immune system to attack diseased cells, is now seen by many as a last hope for critically ill patients who have become resistant to all other forms of treatment and has generated a tremendous amount of interest both within research and among the general population.
This isn’t to say that the approach hasn’t suffered from problems. November last year saw Juno Therapeutics reporting on five deaths that had occurred during their CAR-T clinical trial in 2016, and the FDA lifting a hold they’d previously placed on Cellectis’ Phase I trial following another patient death. Even the CAR-T treatments that have been approved for clinical use have been observed to carry the risk of certain side effects, in particular cytokine release syndrome (CRS), the condition responsible for the Cellectis patient death.
CRS has proven to be difficult to prevent and treat in patients on CAR-T therapies, in part because of the broad collection of symptoms associated with the condition. In some patients, CRS may cause fever or a rash, while in others, it can present as severe neurological problems; as a result, it can be challenging for clinicians to identify the problem. Even once they have determined what’s wrong, the most common treatment for CRS is Genentech’s Actemra (tocilizumab), which suppresses the immune system, but it has not always proven to be effective at eradicating all CRS symptoms.
Actemra was first approved by the US Food and Drug Administration in 2010 for the treatment of rheumatoid arthritis (RA). The drug works by blocking an inflammatory cytokine associated with the condition, interleukin-6 (IL-6), which is known to occur at very high levels in RA patients. After the drug was also proven to be effective at suppressing CRS in CAR-T patients, the FDA approved it for that purpose last year.
The first study, which was carried out by researchers at San Raffaele Hospital in Spain, involved studying mouse models with induced CRS and investigating how they responded to changes in different cytokines. They found that while IL-6 played an important role in the condition, high levels of another cytokine called IL-1 developed several hours before its analogue. Even more importantly, their research indicated that the increased concentration of IL-1 was partially responsible for the later increases in IL-6.
Using this information, the team treated the mice with a different RA treatment, Amgen’s Kineret (anakinra). Kineret, which was originally developed by Amgen and is now marketed by Sobi, was first approved for the treatment of RA in 2001 and is distinct from Actemra in that it has the capacity to enter the brain. This is notable here as it indicates that the treatment has the potential to treat the neurological symptoms of CRS that Actemra cannot.
“In neurotoxicity, there is no advantage to giving an IL-6 inhibitor because it does not cross the blood-brain barrier,” said Attilio Bondanza, co-author of the study, in an interview with The Scientist.
The second study involving IL-1 was carried out by a group of researchers at Memorial Sloan Kettering in New York. They found that existing immune cells in mice were able to produce IL-1, IL-6, and nitric oxide, all of which are involved in the development of CRS, and that by treating the mice with Kineret, they were able to diminish CRS symptoms significantly.
The researchers behind this work are hopeful that their results will prompt clinical trials investigating the safety and utility of using Kineret alongside CAR-T therapies in cancer patients. It is also possible that this improved understanding of the cytokine mechanisms involved in CRS will enable the development of new medications that are able to more effectively treat the condition.