CD19 directed CARs in acute lymphoblastic leukemia: state of the art and beyond

Abstract

The transfer of autologous T cells engineered to express chimeric antigen receptors (CARs) has proven remarkably successful in patients with CD19þ hematological malignancies. Such CARs contain an extracellular anti-CD19 single-chain variable fragment, a transmembrane domain, a costimulatory domain (either 4-1BB or CD28), and the intracellular CD3-zeta signaling moiety. Several clinical trials have demonstrated the activity of this approach in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) (Table 1). On 30 August 2017, the U.S. Food and Drug Administration (FDA) made tisagenlecleucel (CTL019, Kymriah, Novartis), a CD19-directed CAR T cell, the first engineered T cell therapy available in the United States. However, the approval of tisagenlecleucel in ALL is restricted to patients with relapsed/refractory disease up to 25 years of age. The development of these therapeutics in adults has been hampered by lower response rates and several deaths related to CAR T cellassociated toxicities such as cytokine release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES). Lessons learned from CD19-directed CAR T cell clinical trials will facilitate the design of safer trials in ALL. Several conclusions can be drawn from such studies, including: (a) CAR T products can be manufactured for most patients (albeit some products are suboptimal and some patients drop-out due to long manufacturing times); (b) CAR T cells expand very rapidly upon infusion; (c) CRS afflicts most treated patients within hours to days postinfusion and it is associated with brisk elevations of IL-6 and IFN-gamma, most CAR T cell-related complications are transient and manageable; (d) B-cell aplasia in responding patients may be prolonged but not usually permanent; (e) and 70–90% of patients achieve complete remission (CR), frequently with no evidence of minimal residual disease. Thus far, all studies have been uncontrolled single-arm trials and many of them have been conducted at single institutions. While severe CRS rates are similar in both adult and pediatric populations ( 30%) and in both cases manageable, severe CRES rates are higher ( 15% vs. 50%) and several deaths have been reported in trials of adult patients with ALL. Those toxicities, which are more prevalent among patients with higher tumor burden, in combination with lower response rates compared to those observed in pediatric ALL, has thus far hampered the development and prevented the approval of CAR T cell therapy in adult ALL. In fact, tisagenlecleucel (CTL019, Kymriah, Novartis), the only CAR T cell therapy approved in ALL thus far, was approved by the FDA for the treatment of relapsed or refractory ALL in patients up to 25 years of age. The approval of tisagenlecleucel was supported by initial reports showing a CR rate of 90% in a clinical trial that enrolled 25 pediatric and 5 adult patients with ALL [1]. Severe CRS occurred in 27% of patients, frequently in the context of high tumor burden [1]. These results were confirmed in the global ELIANA study [2], in which the ORR among the 75 pediatric patients treated with tisagenlecleucel was 81% (CR 60% and CRi [CR with incomplete bone marrow recovery] 21%). Despite prolonged persistence, the relapse-free survival (RFS) was 59% at 1 year, with a significant number of patients relapsing with CD19-negative disease [2]. CRS occurred in 77% of patients and resulted in ICU admission in 47% of them while 40% of patients experienced CRES, being grade 3 in 13% [2]. In pediatric relapsed/refractory ALL, tisagenlecleucel compares very favorably to the FDA-approved agent clofarabine, which is associated with CR rates of 8–20% and represents the new standard of care in this setting. However, varying levels of efficacy have been reported across trials, likely owing to differences in patient characteristics and CAR T cell designs. When data from the main CAR T cell trials are pooled together, the CR rate (including CRi) among patients with relapsed/ refractory ALL is 77% (Table 1). However, when data are analyzed according to patient age, important differences in efficacy and safety are unveiled. In studies that predominantly enrolled patients of pediatric age or young adults, the CR rate is 85% but it was only 69% when only trials enrolling predominantly adult patients are considered. The inferior results in adult patients are not just due to lower efficacy but also to higher toxicity and mortality. Indeed, most deaths directly attributable to CAR