Though clinical work is ongoing and early, researchers are already considering how to manage potentially fatal neurotoxicities in patients treated with chimeric antigen receptor T-cell therapy
Carl H. June, MD
Researcher are considering how to best manage the toxicities associated with chimeric antigen receptor (CAR) T-cell therapies for patients with cancer, as these therapies begin to be explored across a variety of settings, according to Carl H. June, MD, at the 2015 Society for Neuro-Oncology Annual Meeting.
“What we try to do is treat patients–to keep them out of the [intensive care unit],” said June, Richard W. Vague Professor in Immunotherapy, Perelman School of Medicine at theÂ University of Pennsylvania, during his presentation. “The primary symptoms really are fever, but the clinical toxicity is manifest by hypertension and respiratory failure.”
CAR T-cell therapies have shown complete response rates of more than 90% across a variety of early phase studies for patients with hematologic malignancies. At this time, the two therapies that are furthest along are JCAR015, from Juno Therapeutics, and CTL019, from Novartis. These agents have each received breakthrough therapy designations from the FDA, for their potential in patients with acute lymphoblastic leukemia (ALL). Now, this class of therapy is beginning to be explored in solid tumors and for patients with glioblastoma.
Given his familiarity with the CD19-targeted CAR T-cell therapy CTL019, June specifically addressed the treatment of two toxicities associated with this agent: cytokine release syndrome (CRS) and encephalopathy. In most cases, June noted that both of these AEs are easily reversed, if properly treated.
CRS is a reversible AE that is related to macrophage activation syndrome (MAS), which is characterized by elevated serum ferritin (>500,000 ng/mL) and elevated levels of IFN-gamma and interleukin (IL)-6. To treat this AE, June recommended the use of tocilizumab (Actemra), a recombinant humanized anti—IL-6 receptor antibody.
A single injection of tocilizumab, which is approved for rheumatoid arthritis and juvenile idiopathic arthritis, can eliminate fever from CRS within 4 hours, according to June. Trials are ongoing to determine if the agent can be given prophylactically.
The first two patients to experience CRS with a CAR T-cell therapy, both pediatric patients with ALL, had fevers that started approximately 4 days after infusion and were correlated with increased cytokines (mainly IFN-gamma and IL-6). Additionally, patients in the phase I study for the CAR T-cell therapy also experienced tachycardia and hypertension 4 to 5 days after infusion, along with liver function abnormalities and increased levels of lactate dehydrogenase.
Resolving organ failure took longer in patients with grade 3/4 CRS, June said, but was still reversed in almost all cases. Differences also remain across age groups and disease type, June said, although the reason is unknown.
“In adults with CLL [chronic lymphocytic leukemia], cytokine release syndrome is more delayed than it is with ALL, for reasons that remain obscured,” June observed.
Two patients with multiple myeloma were treated with CTL019 in a pilot study and both experienced CRS. One patient’s CRS was severe and lasted 3 weeks, while the other had a milder event. In most situations, the occurrence of CRS has been linked to better outcomes, for patients treated with CAR T-cell therapies.
The connection between CRS and neurologic AEs is apparent, though not completely understood, June noted. Overall, there are a number of neurologic AEs that have occurred with anti-CD19 CAR T-cell therapy, all of which have a simultaneous or delayed onset with CRS.
Common symptoms of encephalopathy included aphasia, confusion, delirium, and hallucinations, which occurred in 33% of pediatric patients with ALL. Two seizures were also observed.
“In the case of this encephalopathy, it is not associated with response rates–unlike the CRS, which is associated with good responses,” said June, while pointing out that encephalopathy may be related to CD19.
Similar events have been reported with blinatumomab (Blincyto), the anti-CD19 immunotherapy that is FDA-approved for the treatment for Philadelphia chromosome-negative relapsed/refractory B-precursor ALL. The cause of encephalopathy is not completely understood, and this toxicity was generally short lived.
In the phase I pediatric ALL study for a CAR T-cell therapy, encephalopathy often presented after CRS and lasted a median of 7 days, June noted. All patients recovered by day 18 and prior tocilizumab did not prevent the onset of encephalopathy. Two patients had seizures.
Before an anti-CD19 CAR T-cell therapy is approved, researchers and physicians alike hope to have a fuller understanding of how these drugs work and the toxicities associated with them, specifically neurotoxicity. This research will become increasingly important, as this class of therapy moves into new settings with unique targets.