CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia

Abstract

Relapsed and refractory acute lymphoblastic leukemia (ALL) remains difficult to treat, with minimal improvement in outcomes seen in more than 2 decades despite advances in upfront therapy and improved survival for de novo ALL. Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a powerful targeted immunotherapy, showing striking responses in highly refractory populations. Complete remission (CR) rates as high as 90% have been reported in children and adults with relapsed and refractory ALL treated with CAR-modified T cells targeting the B-cell-specific antigen CD19. Distinct CAR designs across several studies have produced similar promising CR rates, an encouraging finding. Even more encouraging are durable remissions observed in some patients without additional therapy. Duration of remission and CAR-modified T-cell persistence require further study and more mature follow-up, but emerging data suggest these factors may distinguish CAR designs. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome (CRS), posing a unique challenge for toxicity management. This review will discuss the current landscape of CD19 CAR clinical trials, CRS pathophysiology and management, and remaining challenges.

Figure 1

CAR structure, according to signaling domains. CAR molecules link an extracellular single-chain variable fragment (scFv) to intracellular signaling domains. The intracellular component includes the CD3ζ intracellular signaling domain of the T-cell receptor either alone (first generation) or in combination with 1 (second generation) or 2 (third generation) costimulatory domains. Reprinted with permission from Maus et al.

Figure 2

Second-generation CAR used in current clinical studies at Penn and CHOP. CTL, cytotoxic T lymphocyte; MHC, major histocompatibility complex. Reprinted with permission from Barrett et al. © Sue Seif

Figure 3

Event-free survival in 30 children and adults treated with CTL019 therapy. Of this group, 5 patients who entered a CR went on to further therapy, 3 of whom received an allogeneic bone marrow transplant. The fourth had refractory T-cell ALL aberrantly expressing CD19, entered remission after CTL019, and subsequently underwent donor lymphocyte infusion. She remains in remission >1 year later. The fifth patient developed myelodysplastic syndrome and received therapy for this condition (this was scored as an event, but she did receive further therapy in ALL remission and was counted among the 5). The rest have not received further therapy to consolidate their remissions. EFS, event-free survival. Figure adapted from Maude et al with permission.