Descripción del proyecto
Tratamientos nuevos para la leucemia resistente
La leucemia linfoblástica aguda de precursores B (LLA-B) es un tipo de cáncer infantil con un buen pronóstico. Sin embargo, la presencia de reordenamientos del gen de la leucemia de linaje mixto (LLM) se asocia con una ausencia de respuesta al tratamiento y recidiva. Pese a que la inmunoterapia mediante linfocitos T-CAR CD19 ha mostrado una gran eficacia frente a la LLA-B resistente, las recidivas notificadas tras el tratamiento hacen necesario descubrir tratamientos celulares alternativos. El objetivo del proyecto financiado con fondos europeos IT4B-ALL es desarrollar nuevas estrategias terapéuticas contra la LLA-B resistente. Los investigadores han desarrollado un anticuerpo contra el antígeno neural-glial 2 (NG2), un proteoglucano transmembrana que se expresa únicamente en la LLA-B con reordenamientos del gen de la LLM. También han generado nuevos linfocitos T-CAR que se dirigen al antígeno de superficie CD22 o NG2 junto a CD19 para ofrecer una mayor eficacia.
Objetivo
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
Ámbito científico
Programa(s)
Régimen de financiación
ERC-POC - Proof of Concept GrantInstitución de acogida
08916 Badalona
España