Road trip to remission with CARs

What happens when a novel drug isn’t a drug, but a replicating, cell-based product? In this issue of Blood, Mueller et al performed the first formal cellular kinetic analyses of tisagenlecleucel (CTL019) in patients with acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL) using pharmacokinetic principles to characterize the movement and persistence of cell-based therapies and examine its relationship to efficacy and safety.¹  Pharmacokinetics, the movement of a drug into, through, and out of a body, are vital to understanding the appropriate use of a novel drug, but the movement and persistence of living cellular therapy products cannot be expected to follow conventional rules. The recent US Food and Drug Administration approval of CTL019 for pediatric ALL is changing the landscape of treatment of hematologic malignancies, down to how we define a drug.

CTL019 is highly efficacious in pediatric patients with relapsed or refractory ALL, with a reported overall response rate of 82% to 93%.^2,3  Likewise, in diffuse large B-cell lymphoma, a best overall response rate of 59% (43% complete response, 16% partial response) was reported,⁴  and in CLL, 53% (35% complete response, 18% partial response).⁵  However, rapid in vivo expansion of CTL019 and other T-cell therapies is marked by the development of cytokine release syndrome (CRS), characterized by high levels of circulating inflammatory cytokines, with interleukin-6 chief among them. Ninety percent of ALL patients, 88% of CLL patients, and 57% of diffuse large B-cell lymphoma patients developed some CRS at peak T-cell expansion. In most cases, CRS can be managed with supportive care, or, if needed, antibodies such as tocilizumab, which blocks interleukin-6 receptor signaling.^6,7  The association between response, CRS, and robust CTL019 expansion has been previously described by investigators at the University of Pennsylvania and is further explored here.

The authors analyzed samples from 103 patients enrolled in 3 clinical trials that included both pediatric and adult patients with ALL and adult patients with CLL. All patients received either a single dose of CTL019 or 2 to 3 fractionated doses within the first 28 days. Following peak infusion levels, there was an initial transient decline in circulating CTL019 transgene as the cells trafficked throughout the peripheral blood, bone marrow, and other tissues, followed by a rapid expansion of circulating CTL019 cells. Although there was a decline over the subsequent weeks and months, cells were detectable in some patients beyond 1 year, and responding patients tended to have higher cumulative exposure. Similarly, CTL019 transgene was seen in the bone marrow at higher levels and for a longer time in responding patients, and, in some cases, was detected more than 2 years after infusion. High CTL109 transgene levels were also detectable in the cerebral spinal fluid, and there was no significant relationship between concentration of transgene and neurologic toxicity. In ALL patients with a higher preinfusion tumor burden, increased expansion was noted, and these patients also tended to have higher CRS grade and neurologic toxicity. Tocilizumab administration did not abrogate CTL019 expansion, which has important implications for the management of patients with CRS.

Chimeric antigen receptor (CAR) T cells are a living drug with distinct behavior, but the authors were able to use traditional pharmacokinetic analysis methods to describe that behavior and correlate it with preinfusion tumor burden, response, and adverse effects. This analysis provides insight into the kinetics and trafficking of CAR T cells and will surely serve as an important guide as the field of cellular therapy expands.