Andrew J. Roth

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.

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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

June Provides Insight Into Managing AEs From CAR T-Cell Therapies

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 elicited a 91% complete remission rate in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL), according to results from a phase I trial presented at the 2015 AACR Annual Meeting.

In the intent-to-treat population, complete remissions were observed in 20 of 22 patients, as measured by flow cytometry. Complete remissions were seen with all doses of JCAR017 and in patients treated with prior CD19-targeted therapy. Severe neurotoxicity and/or severe cytokine release syndrome was observed in 8 patients. In total, 4 patients have relapsed—only one of which had CD19-positive disease.

“The 91% remission rate in this phase I study of JCAR017 is highly encouraging, particularly when considering these pediatric patients failed to respond to standard treatments,” Michael Jensen, MD, said in a statement. “Based on these results we are eager to advance this study, and to continue advancing the use of cell therapies to change how we treat cancer and provide patients the opportunity for better treatment options.”

Jensen is the director of the Ben Towne Center for Childhood Cancer Research at Seattle Children's Research Institute and scientific co-founder of Juno Therapeutics, the company developing the therapy. JCAR017 is being explored in an ongoing phase I/II study for pediatric and young adult patients with relapsed/refractory CD19-positive leukemia at the Seattle Children's Hospital.

The study plans to enroll 80 patients. The phase I portion enrolled patients who had undergone an allogeneic hematopoietic cell transplant. The second phase of the study is open to patients, regardless of prior transplant status (NCT02028455).

"Given the impressive clinical results with this defined cell product candidate, we are encouraged to begin testing of JCAR017 in adult patients with B cell malignancies, including non-Hodgkin lymphoma, later this year," Hans Bishop, chief executive officer of Juno Therapeutics, said in a statement.

In addition to JCAR017, Juno currently has three other CAR and T cell receptor therapies being evaluated in clinical trials. The furthest along is JCAR015, which received a breakthrough therapy designation from the FDA as a treatment for patients with relapsed or refractory B-cell ALL in November 2014.

JCAR015 is being investigated in two phase I clinical trials. One trial is examining the agent in precursor B cell ALL, the setting in which the agent gained its orphan drug designation (NCT01840566). In the other trial, patients with relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL) are being treated with high dose therapy and autologous stem cell transplantation followed by infusion of JCAR015 (NCT01044069).

Future clinical trials are planned to explore Juno’s CAR T cell therapies in combination with immune checkpoint inhibitors. Recently, Juno and MedImmune, the biologics research and development arm of AstraZeneca, announced an agreement focused on the clinical development of combination strategies.

Under the non-exclusive collaboration, MedImmune and Juno will jointly fund a phase Ib study that will explore one of Juno's CD19-directed CAR T cell therapies in combination with the PD-L1 inhibitor MEDI4736 as a treatment for patients with NHL. Exact details of the study were not released. It is expected to begin later this year.

"We believe combination strategies such as this will help us better understand the full potential of our engineered T cell platform in both hematological and solid tumor settings," Mark W. Frohlich, MD, executive vice president, Research & Development, Juno Therapeutics, said in a statement.

MEDI4736 is currently being evaluated in phase III clinical trials. The agent is being looked at alone and in combination with the CTLA-4 antibody tremelimumab across the spectrum of non-small cell lung cancer and in patients with head and neck cancer who have failed prior chemotherapy.

Competition in the field of immuno-oncology has resulted in collaborations between several pharmaceutical companies, outside of the Juno deal. This is evident in the field of CAR-modified T-cell therapy, where collaborations exist between Novartis and the University of Pennsylvania (CTL019) and between Kite Pharma and the NCI (KTE-C19).

In the pediatric oncology space, results from the breakthrough therapy CTL019 were presented at the 2014 ASH Annual Meeting and demonstrated similar findings to those announced for JCAR017. In this phase I trial of 39 pediatric patients with relapsed/refractory ALL, CTL019 demonstrated a 92% complete remission rate. In total, 85% of patients who achieve a complete remission tested MRD-negative by flow cytometry.

The chimeric antigen receptor T-cell therapy JCAR017 elicited a 91% complete remission rate in pediatric patients with relapsed/refractory acute lymphoblastic leukemia.


Andrew J. Roth

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June Provides Insight Into Managing AEs From CAR T-Cell Therapies

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