Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) have an urgent and high unmet medical need, because of their poor prognosis. “CAR T-cells, I think, fit that need,” Dr Porter said.
There are variations between anti-CD19 CAR constructs. Tisagenlecleucel (Kymriah) uses a 4-1BB co-stimulatory domain, whereas axicabtagene ciloleucel (Yescarta) uses CD28. The manufacturing of CAR T-cells takes 2 to 3 weeks.
“Technology is being developed to shorten this time period, so in some cases, we hope that cells will be available as early as a week,” Dr Porter said.
Two large multicenter clinical trials have demonstrated the positive impact of tisagenlecleucel (the JULIET study) and axicabtagene ciloleucel (the ZUMA-1 study) in large B-cell lymphoma. Both studies led to the FDA approval of these 2 CAR T-cell therapies for the treatment of patients with relapsed or refractory DLBCL.
A third CAR T-cell therapy, lisocabtagene maraleucel, is under investigation for relapsed or refractory DLBCL.
“Regardless of some of the differences in constructs in these different products, outcomes are very similar across platforms,” Dr Porter said. “The best overall response rate varies somewhere between 50% to 80%, complete responses between 40% to 55%, and ongoing or sustained complete responses, about 30% to 35%.”
Many of the remissions obtained with tisagenlecleucel in the JULIET clinical trial were sustained, he observed. Relapses tend to be early, “and there appears to be a plateau in the survival curves, suggesting that many of these patients have long-term sustained remissions, and I venture to say, may even be cured when there’s no other potentially curative therapy for them,” Dr Porter emphasized.
Real-World Experience
The real-world experience with axicabtagene ciloleucel was described by Nastoupil and colleagues, who conducted a survey of 17 US centers with 165 patients who received this CAR T-cell therapy (46 patients did not receive their CAR T-cells as intended). The 30-day overall response rate (ORR) was 79% and the 30-day complete response rate was 50%. At 100 days, 49% of the patients had a complete response. These response rates were similar to those obtained in the ZUMA-1 trial.
Of note, only 51% of the patients in this real-world survey met the ZUMA-1 eligibility criteria. “This is exactly what people anticipated,” Dr Porter said. “We are now starting to treat patients who are sicker, who have comorbid disease, and don’t meet entry criteria for a trial,” he said. “Despite that, the overall response rates and complete responses seem to be preserved.”
A second real-world experience of the commercial use of axicabtagene ciloleucel in 76 patients mirrored the survey results of Nastoupil and colleagues.
Adverse events were also similar between the clinical trials and the real-world report, with rates of severe cytokine release syndrome in the range of 7% to 17% and other neurologic events of approximately 31%.
Enhancing Response
In patients with acute lymphoblastic leukemia, 90% of patients achieve a complete response, whereas in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma, the complete response rate is only 25% to 35% and 30% to 40%, respectively.
“Relapse isn’t the big issue,” Dr Porter said. “The big issue is getting more patients to respond. It seems somewhat intuitive to think about checkpoint inhibition.”
Because checkpoint activity may limit CAR T-cell response, checkpoint inhibitors and CAR T-cell therapy may have potential synergies, he said. “Sequential CTL019 [tisagenlecleucel], or CAR T-cells, with checkpoint inhibitor therapy, we think is going to be a very promising approach, and has led to a phase 1/2 study of pembrolizumab [Keytruda] in patients failing to respond to CAR T-cells,” he said.
Ibrutinib (Imbruvica) may also enhance CLL response to tisagenlecleucel. T-cells from patients with CLL who receive ibrutinib for 6 to 12 months exhibit superior proliferative capacity in vitro, superior survival in vitro, and reduced PD-1 expression compared with baseline values. Ibrutinib also reduces expression of inhibitory and checkpoint molecules on CLL cells, making them better targets for CAR T-cells and may enhance tisagenlecleucel expansion, resulting in better CLL cell death, Dr Porter said.
In a clinical trial of ibrutinib combined with CAR T-cells in 20 patients with highly refractory CLL, the ORR at 3 months was 71% and the complete response rate was 43%; in 94% of the patients, all CLL was cleared from their bone marrow. At 12 months, 7 of 11 patients tested were MRD-negative. “We think this is a very promising approach, showing that many patients can achieve MRD-negative state,” Dr Porter concluded.