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