Cellular therapies in acute lymphoblastic leukemia

Abstract

The majority of adult patients with acute lymphoblastic leukemia (ALL) will die from the disease. Although the prognosis for pediatric patients is significantly better than for adult patients with ALL, the prognosis for patients with relapsed or refractory disease is poor in all cases. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a related donor offers a significant therapeutic benefit for pediatric patients, although the benefit of this therapy to adults with ALL is less established. Because most patients lack a suitable related donor, alternative approaches to allo-HSCT, including umbilical cord blood, and unrelated and haploidentical allo-HSCT, have been investigated in the clinical setting. Although treatment with donor-derived T-cells, so-called 'donor lymphocyte infusion', has demonstrated poor outcomes in patients with relapsed ALL following HSCT, modified adoptive T-cell regimens, including the infusion of enriched tumor-targeted donor T-cells and genetically targeted T-cells, are currently under clinical investigation. In addition, the resistance of ALL tumor cell lines to NK-cell-mediated lysis may be overcome by the genetic modification of NK cells to target ALL tumor cell antigens, and this approach will be evaluated in an upcoming clinical trial. Whether these novel adoptive cell therapies will ultimately result in improved clinical outcomes remains to be determined.

Figure 1. Generation of chimeric antigen receptor-modified tumor-targeted T-cells

T-cells may be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CARs are most commonly generated by cloning the heavy (V_H) and light (V_L) chain coding regions from a mouse hybridoma, producing a mAb specific to the targeted antigen (A). The resulting coding regions are fused with a short linker peptide to generate a scFv coding domain that is subsequently fused to a TM domain, which may be derived either from CD8, or from domains coding the TM and cytoplasmic signaling domains of costimulatory receptors, including CD28, 4-1BB and OX-40, followed most typically by the coding sequence of the cytoplasmic signaling domain of the TCR ζ chain (B). The resulting CAR coding sequence is most commonly subcloned into a retroviral vector to generate CAR+ viral particles (C). Isolated and activated T-cells are subsequently retrovirally transduced with the CAR construct, generating a population of T-cells that express the CAR (D). The resulting CAR+ T-cells recognize and lyse tumor cells that express the CAR-targeted antigen (E). scFv single-chain variable-fragment antibody, TCR T-cell receptor, TM transmembrane