Analytical Modeling Study of Acute Lymphoblastic Leukemia Treatment with Blinatumomab and Tyrosine Kinase Inhibitors
Open Access
- Author:
- Onweller, Lauren
- Area of Honors:
- Biomedical Engineering
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Cheng Dong, Thesis Supervisor
Meghan Vidt, Thesis Honors Advisor
Justin R Pritchard, Thesis Supervisor - Keywords:
- TKI
BiTE
Cancer
Combination Therapy
Matlab - Abstract:
- Acute Lymphoblastic Leukemia (ALL) is a blood-based cancer that accounts for 30% of all pediatric cancer patients and is the second most common type of acute leukemia in adult cancer patients [1]. ALL is an aggressive form of cancer with an average survival rate of only 5 years, suggesting that novel treatment options are needed. Treatment methods such as chemotherapy are often unsuccessful at treating ALL, as they are not specific and can lead to relapses [2]. Two therapeutics of interest are bispecific T cell engagers (biTEs) and tyrosine kinase inhibitors (TKIs), both of which address the specificity issues that arise with chemotherapy. BiTEs, also known as bispecific antibodies, are comprised of two monoclonal antibodies held together by a peptide linker. One end of the biTE binds to CD3+ T cells and the other end binds to CD19+ B cells. These can be used in cancer therapeutics to recruit immune cells to the site of cancer cells. TKIs work to inhibit their respective tyrosine from phosphorylating tyrosine residues and inhibit pathways downstream of the phosphorylation in the malignant B cells. There are ongoing clinical trials on treatment of Philadelphia Chromosome positive (Ph+) B cell ALL with the combination of TKIs and the biTE blinatumomab. One clinical trial investigated treating the ALL with blinatumomab and ponatinib and the other investigated blinatumomab with dasatinib. The rationale behind this combination is to inhibit kinase activity in malignant B cells while also promoting an immune response through activating T cell receptors and recruiting T cells [3]. However, previous studies have found that when used in combination, TKIs involved with the Src family kinases and biTEs have an antagonistic effect on cancer treatment [4, 5]. Through in vitro experimentation and mathematical modeling, it is possible to explore the antagonism mechanism of TKIs and biTE combination therapy.