InTheMLLrBALL · Innovative Therapeutic Strategies for Mixed Lineage Leukemia-rearranged B-cell Acute Lymphoblastic Leukemia

Innovative Therapeutic Strategies for Mixed Lineage Leukemia-rearranged B-cell Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is the commonest cancer in children and many B-ALL patients are refractory to chemotherapy and eventually relapse. Adoptive transfer of T-cells engineered to express an artificial chimeric antigen (Ag) receptor (CAR) targeting a tumor cell surface-specific Ag is a promising approach for Cancer Immunotherapy. In B-ALL, CAR T-cells targeting CD19 have generated unprecedented results, and ~50% of treated patients are disease-free after 1 year. However, relapse after treatment is common. Moreover, the expression of CD22 has been demonstrated in B-ALL cells as well as in patients who relapse as CD19- after CD19-CAR T-cell therapy. Consequently, a CD22-CAR T-cell approach has been recently developed, and preliminary clinical results in refractory/relapse (R/R) B-ALL are promising; however, relapse also occurred. A strategy to offset Ag-loss relapse is to modify T-cells with one CAR molecule containing two different binding domains in tandem. Therefore, tandem CAR T-cells targeting both CD19 and CD22 may overcome Ag-loss escape and reduce the risk of relapse in B-ALL. Immuno checkpoints (IC) receptors such as PD-1, CTLA-4, LAG-3, and TIM-3 regulate immune function homeostasis, but many cancers overexpress their ligands (Ls) as immune-regulatory mechanism to achieve immune escape. Moreover, the involvement of tumor microenvironment in the loss of CAR T-cell function by PD-1/PD-L1 has also been suggested. To date, there is a paucity of clinical data showing that blockade of IC can enhance CAR-T cell function. In the setting of B-ALL, recent studies suggest that B-ALL cells seem to regulate T-cell function through PD-1/PD-L1 axis, thus impairing the therapeutic efficacy of T-cells against B-ALL cells. Overall, these studies underscore the need to investigate the role of IC molecules in the B-ALL cell response treatment. B-ALL originates in the bone marrow (BM), and the BM microenvironment (BMM) is particularly important in B-ALL given the high dependence of leukemic cells on external factors for proliferation and survival. The BM is also the primary site where residual leukemic cells survive during standard chemotherapy, and is the most frequent location of B-ALL relapse. Mesenchymal stromal cells (MSC) are vital constituents of the BMM and are involved in drug resistance of B-ALL cells during chemotherapy. The successful function/persistence of CAR T-cells within the host depend on complex in vivo processes and, in recent years, it has been extensively demonstrated that MSC regulate T-cells by modifying their activation, proliferation, and effector functions. However, the impact of BM-MSC on CD19-CAR T-cells, that are likely to experience the same loss of function/persistence as T-cells is understudied. The rationale for launching this project was to develop a new CAR T-cell immunotherapy for B-ALL patients, who otherwise have no current alternative treatment. In the time of this Marie Skłodowska-Curie Actions Individual Fellowship, by using both in vitro and in vivo approaches, I generated a novel tandem CD22/CD19-CAR for the treatment of R/R B-ALL. In parallel, I contributed to characterized IC axes in B-ALL to decide which of them has the major implication in B-ALL to develop future immunotherapies. Finally, I studied the influence of BM-MSC from B-ALL patients in the activity of CD19-CAR T-cells to understand better the interplay between T-cells, B-ALL cells and BM-MSC to improve the efficiency of this immunotherapy. In general, the findings of this project not only generate frontier knowledge on the disease, they are also very important for society. In particular, for patients with B-ALL who do not have current alternative treatment because the findings of this project provide key information for the clinical translation of a CD22/CD19-CAR for B-ALL.

Data: CORDIS, © European Union