2.The Development of Drugs and Treatments of ALL in Recent Years
ALL is prone to occur in children around 5 years old and adults around 50 years old, it is mainly considered to be a kind of pediatric leukemia, accounting for 80% of cases in children and 20% in adults(Jabbour, O’Brien, Konopleva & Kantarjian, 2015). The 5-year OS rate for children is about 90%, compared to only 30% to 40% for adults and elderly patients(Inaba & Mullighan, 2020). The chemotherapeutics used in clinical to treat ALL include glucocorticoids, microtubule inhibitors, anthracyclines, purine and folate antimetabolites, asparaginase and DNA alkylating agents. In recent years, great progress has been made in therapeutic target discovery and drug development, such as antibody-drug conjugate (ADC) inotuzumab ozogamicin. Inotuzumab ozogamicin is used to treat relapsed or refractory CD22-positive precursor B-cell ALL (pre-B ALL), and calaspargase pegol-mknl (Cal-PEG), the asparagine-specific enzyme, is used to treat children and adolescents ALL. It is worth mentioning that blinatumomab, which was approved by the FDA in 2014, is the world’s first approved CD19 drug by the FDA for the treatment of Ph- relapsed/refractory pre-BALL. At present, the main clinical methods to treat ALL include early intensive therapy, hematopoietic stem cell transplantation (HSCT), cranial radiation therapy (CRT), Central Nervous System (CNS)-directed chemotherapy, and chimeric antigen receptor T-cells (CAR-T). Intensive therapy has significantly improved the prognosis of pediatric patients, but has the disadvantage of long-term sequelae. In addition, only 30-40% of adult ALL patients achieve long-term remission(Jabbour, O’Brien, Konopleva & Kantarjian, 2015), elderly patients and patients with high-risk subtypes of leukemia, such as early T-cell precursor ALL(ETP-ALL), often cannot tolerate such treatment regimens and have a poorer prognosis(Ballesteros-Arias, Silva, Paiva, Carbonetto, Faísca & Martins, 2019). Although multi-drug chemotherapy has certain therapeutic advantages, many patients still relapse and develop refractory leukemia(Gianfelici et al., 2016), and only 20% of relapsed pediatric patients can be cured(Richter-Pechańska et al., 2017). In addition, the use of genotoxic drugs in the treatment process may lead to secondary malignancies(Teepen et al., 2017). Thus, we need more effective and less toxic treatments to improve the prognosis of ALL patients. One report replaced chemotherapy with targeted therapy, dasatinib combined with dexamethasone to treat ALL, and then performed two cycles of bispecific anti-CD3 and anti-CD19 antibody blinatumomab, proving that targeted therapy can avoid the induction of combined chemotherapy, with an OS of 95% and a disease-free survival of 88%(Foà et al., 2020). Targeted drugs can pinpoint and identify cunning tumor cells, delivering precise and thorough strikes with few ADR cases, without damaging their own tissues. However, targeted drugs are expensive and mostly are not suitable for all cancer patients. Animal models can replicate human diseases in a short period of time, which makes it more convenient and effective to understand the occurrence and development of human diseases and offers the measures to prevent and overcome diseases, therefore laying the foundation to develop potential targeted drugs, individualized treatment and new therapeutic tools.
3. Spontaneous ALL Animal Models
Some strains of mice will spontaneously develop leukemia during growth, and only need to screen them to obtain the desired animal model. AKR mice are the strain with the highest incidence of leukemia, and C57BL mice can also be used for screening. AKR strains have a high incidence of lymphocytic leukemia, with a prevalence of 70%-90%, and were commonly used for lymphocytic leukemia research before the development of transgenic technology and xenograft models. As early as 1975, researchers studied whether the genetic factors of AKR mouse strain played a role in the occurrence of leukemia. Later, researchers studied the sequence characteristics of AKR mouse leukemia virus substrain and the structure of the integrated recombinant genome in tumor tissues and found that AKR, as a spontaneous leukemia mouse, was born with a carcinogenic RNA virus(Quint, Quax, van der Putten & Berns, 1981). Compared with tumors induced by experimental methods, the clinical symptoms of spontaneous models and human tumors are more similar, and the conditions for tumor occurrence are more natural. However, the etiology of spontaneous models is quite different from the pathogenesis of human diseases, which are mainly caused by genetic factors. Moreover, such model is easily affected by environmental factors, and the model takes a long time to establish and has poor stability, so it is rarely used in practice. In order to establish an animal model with a short incubation period and the tumor that is more similar to human cancer in pathogenesis, researchers have explored induced animal models.
4.Induced ALL Animal Models