Project description
Novel therapies for refractory leukaemia
B cell acute lymphoblastic leukaemia (B-ALL) is a childhood cancer with good prognosis. However, the presence of rearrangements of the mixed lineage leukaemia (MLL) gene is associated with no response to therapy and relapse. Although immunotherapy in the form of CD19 CAR T cells has shown great efficacy against refractory B-ALL, reported relapses after treatment necessitate alternative cell therapies. The aim of the EU-funded IT4B-ALL project is to develop novel treatment strategies against refractory B-ALL. Researchers have developed an antibody against the neuron-glial antigen-2 (NG2), a transmembrane proteoglycan solely expressed in B-ALL with MLL rearrangements. They have also generated novel CAR T cells that target the CD22 surface antigen or NG2 alongside CD19 for improved efficacy.
Objective
B-ALL is the commonest cancer of childhood. There remain childhood B-ALL subgroups with dismal prognosis such as infant B-ALL and B-ALL carrying MLL rearrangements (MLLr). In addition, the prognosis of adult B-ALL is worse, and refractory/relapse (R/R) B-ALL remains dismal. CD19-targeted immunotherapies have emerged as promising therapeutic approaches for R/R B-ALL. CD19 CAR T-cells have shown impressive efficacy in R/R B-ALL. However, relatively rapid relapses are frequently observed, a proportion of them losing CD19 expression upon CAR19 T-cell therapy due to massive antigen pressure over CD19, resulting in a myeloid lineage switch in MLLr B-ALL, or the selection of CD19-/CD34+ preleukemic progenitors. Further CD19-targeted therapy is thus ineffectual for CD19neg R/R B-ALL.
Our overarching goal is to provide novel therapeutic options for (R/R) B-ALL.Targeting surface antigens whose expression, opposite to CD19, are commonly retained at relapse is a valid strategy to circumvent the loss of CD19 found in (R/R) B-ALL after CD19-targeted therapies. Recent work funded by my ERC-2014-CoG has identified NG2 and CD22 as key antigens to be targeted in (R/R) B-ALL. First, both antigens are retained in CD19neg R/R B-ALL. Second, NG2 is solely expressed in MLLr B-ALL, and is associated with CNS infiltration, aggressiveness and glucocorticoid resistance. Third, CD22 is a pan-B marker expressed developmentally earlier than CD19, and CD34+CD22+CD19- cells may represent pre-malignant progenitors escaping the CD19-targeted pressure. These results have just been protected by a European Patent (EPI173825514), and are the proof-of-principle demonstration of NG2 & CD22 representing promising immunotherapeutic targets, when combined with CD19 for both MLLr & MLL-germline B-ALL, respectively. Here we propose to consolidate preclinical work and GMP production of anti-NG2 monoclonal antibody and NG2/CD19 and CD22/CD19 CAR T-cells to launch a PhaseI academic clinical trial for R/R B-ALL
Fields of science
Programme(s)
Funding Scheme
ERC-POC - Proof of Concept GrantHost institution
08916 Badalona
Spain