Novel CAR T-Cell Approach Reduces Toxicities, Retains Efficacy

Nancy A. Melville

April 26, 2019

A new way of making chimeric antigen receptor (CAR) T cells reduces toxicity, which could lower the overall costs of treatment with these hugely expensive products.

In preliminary research, lymphoma patients who were treated with a novel modification of anti-CD19 CAR T cells showed significant reductions in the potentially severe side effects that are a risk with the otherwise breakthrough cancer therapy, and there were no signs of compromised efficacy.

"Toxicities are currently the biggest barrier to the use of CAR T-cell therapy," said senior author Si-Yi Chen, MD, PhD, of the of the University of Southern California (USC) Norris Comprehensive Cancer Center and professor in the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC, in Los Angeles, in a press statement.

"My hope is that this safer version of CAR T-cell therapy could someday be administered to patients in outpatient settings," Chen said.

The majority of patients show a complete response after just a single infusion of CD19-targeted CAR T-cell therapy. However, a potentially serious side effect is cytokine release syndrome (CRS), in which the rapid proliferation of CAR T cells releases a flood of cytokines, posing the risk for multiorgan damage and often necessitating a stay in the intensive care unit.

Rates vary, but CRS can occur in more than 50% of patients.

To counter those effects, Chen and colleagues engineered a new anti-CD19 molecule with modifications designed to slow the proliferation of the cytokines and give the body more time to eliminate the cytokines from the blood.

In the phase 1 trial, published this week in Nature Medicine, 25 patients with refractory B-cell lymphoma were treated with the novel therapy, which was administered in low, medium, or high doses.

Following the treatment, there were no reports of CRS greater than grade 1 among the 25 patients, and there was no evidence of neurologic toxicities, which typically occur in more than 25% of patients who undergo treatment with CAR T cells.

Although the study was not designed to assess efficacy, the authors noted that 6 of the 11 patients (54.5%) who were treated with the highest dose achieved complete remission.

The median duration of response among the six patients who achieved complete remission was greater than 181 days (range, 162–290 days), and for 5 of the 6 patients, complete remission was ongoing at the time of publication.

"This is a major improvement," Chen said. "We've made a new CAR molecule that's just as efficient at killing cancer cells, but it works more slowly and with less toxicity."

The CAR T-cell process involves harvesting immune T cells from the patient's blood and then modifying them in a laboratory to produce CARs on their surface. When reinfused into the patient, the CAR T cells are able to recognize and latch onto cancer cells, destroying them.

In engineering their novel molecule, Chen and his colleagues worked with the prototype of the US Food and Drug Administration–approved anti-CD19 BBZ CAR T cell (Kymriah, Novartis).

They named their improved variant CD19-BBZ(86) and say the next steps should further explore mechanisms and clinical implications.

"A comprehensive investigation is needed to mechanistically reveal the features of signaling and activation in CD19-BBz(86) CAR T-cells," the investigators say. "Additionally, multicenter clinical trials are warranted to evaluate the safety and efficacy of this new CAR T cell therapy."

Findings Are Early but "Intriguing"

Although preliminary, the study represents an important addition to the ongoing efforts to make CAR T-cell therapy safer, said Michel Sadelain, MD, PhD, founding director of the Center for Cell Engineering and head of the Gene Transfer and Gene Expression Laboratory at Memorial Sloan Kettering Cancer Center, in New York City, who was approached for comment.

"It's not a definitive study because it's rather small, and importantly, the follow-up is still limited in time," he told Medscape Medical News. "However, it's intriguing and is definitely something to watch going forward."

The major concern in attempting to lower toxicity by reducing cell strength is that efficacy will be compromised, but the early findings look encouraging, he said.

"They still did get complete responses in 6 of the 11 patients receiving the highest dose, which is in line with current CAR T-cell therapies, so the responses do not appear to be reduced, and importantly, the toxicity is limited," Sadelain said.

A key question will be whether the results will be seen in a larger series with a broader range of patients, Sadelain said. He noted that CRS appears to be a greater risk for patients undergoing CAR T-cell treatment for leukemia, rather than lymphoma.

"It will be important to see how many eventually relapse — did the reduction in toxicity ultimately come at a cost of reducing efficacy in these patients? If it holds up, this will be a very positive event for CAR T-cell therapy," Sadelain said.

Other Efforts to Tackle CRS Underway

Chen and colleagues aren't the only investigators working to reduce the risk for CRS in patients undergoing CAR T-cell therapy — among several others are researchers at Sadelain's own center, Sloan Kettering, where they are investigating combining interleukin-1 (IL-1) blockade with CAR T cells.

That research, which is still preclinical, is described in a study published last year in Nature Medicine. That article describes the establishment of a mouse model for CRS — a model that Chen and his colleagues used in developing their CD19-BBz(86) CAR T cells.

"Until recently, there was no mouse model that could mimic CRS. For some reason, it doesn't occur much in mice, but we found a way to mimic the disease and create a mouse model for it," Sadelain explained.

As the research advances, the next steps will be to compare the approaches, he added.

"We will hopefully be able to compare the CAR T-cell/IL-1Ra combination with this weakened CAR approach and see what the pros and cons are," he said.

Costs Are a Key Issue

Among the most pressing factors driving the urgency in finding a way to prevent CRS is the significant role CRS plays in the costs of CAR T-cell therapy, which are already notoriously high.

As recently reported by Medscape Medical News, real-world data show that costs for the treatments can range from a third to a half million dollars; the median 15-day hospital stay can exceed $85,000, but the cost can reach nearly $250,000 for younger patients. CRS, the management of which can place a heavy burden on resources, adds further to that cost.

"[CRS] doesn't occur in all patients, but when it does, it significantly increases costs, so I think it's good news that data are emerging on several means to potentially control the toxicity," Sadelain said.

The study was supported by the Marino Biotechnology Corp, a private donation from Yi-Lin Zhu, and grants from the National Natural Science Foundation of China. Sadelain has disclosed no relevant financial relationships.

Nat Med. Published April 22, 2019. Abstract

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