Descrizione del progetto
Nuove terapie per la leucemia refrattaria
La leucemia linfoblastica acuta a cellule B (B-ALL) è una malattia tumorale infantile con prognosi buona. Tuttavia, la presenza di riarrangiamenti del gene della leucemia a lignaggio misto (MLL) si associa a nessuna risposta alla terapia e recidiva. Sebbene l’immunoterapia sotto forma di cellule T CAR CD19 abbia mostrato una grande efficacia contro la B-ALL refrattaria, le recidive riportate dopo il trattamento richiedono terapie cellulari alternative. L’obiettivo del progetto IT4B-ALL, finanziato dall’UE, è quello di sviluppare nuove strategie di trattamento contro la B-ALL refrattaria. I ricercatori hanno sviluppato un anticorpo contro l’antigene neurone-gliale-2 (NG2), un proteoglicano transmembrana espresso esclusivamente nella B-ALL con riarrangiamenti MLL. Hanno inoltre generato nuove cellule T CAR che hanno come bersaglio l’antigene di superficie CD22 o NG2, insieme al CD19, per una maggiore efficacia.
Obiettivo
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
Campo scientifico
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Meccanismo di finanziamento
ERC-POC - Proof of Concept GrantIstituzione ospitante
08916 Badalona
Spagna