Combinational Therapy for Acute Lymphoblastic Leukemia with Tyrosine Kinase Inhibitors and Bispecific T Cell Engagers In Vitro
Open Access
- Author:
- Shaffer, Mikayla
- Area of Honors:
- Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Cheng Dong, Thesis Supervisor
Timothy J Jegla, Thesis Honors Advisor
Justin R Pritchard, Thesis Supervisor - Keywords:
- Acute Lymphoblastic Leukemia
Bispecific T Cell Engagers
Tyrosine Kinase Inhibitors - Abstract:
- Acute Lymphoblastic Leukemia (ALL) is the second most common acute leukemia in adults and has a poor prognosis in most adult cases. Combinational therapies utilizing different pharmacological mechanisms have provided new momentum to developing efficient treatments for aggressive cancers such as ALL. There are two ongoing clinical trials testing combination treatments of a SRC family tyrosine kinase inhibitor (SRC TKI) with blinatumomab, a bispecific antibody engager (biTE), for adults with Philadelphia Chromosome positive (Ph+) B cell ALL. One trial is testing blinatumomab with ponatinib, and the second trial is testing blinatumomab with dasatinib. Treating ALL with a combination of a biTE and TKIs intends to initiate the immune defense by activating the T cell receptor and inhibiting the SRC family kinase activity in the B cell receptor. However, T cell activation requires kinase signaling; and thus, multikinase inhibitors antagonize the effects of biTEs. Previous studies investigating biTE and SRC TKI combinational therapies have found unfavorable multi-drug interactions in which dual SRC TKIs have an off-target effect on the efficacy of blinatumomab. Our objective was to investigate i) the biological mechanisms that cause off-target effects of TKIs on biTEs and ii) possible rescue pathways for off-target effects of TKIs on biTEs through the addition of interleukins. We found that LCK plays a pivotal role on T cell receptor signaling; however, phosphorylation of LCK on tyrosine 394 is inhibited by SRC TKIs. Results showed that combination of the SRC TKIs, such as dasatinib/ponatinib with blinatumomab, inhibits the phosphorylation of LCK on Tyrosine 394. Additionally, we found that the addition of interleukins 2, 7, and 15 to dasatinib/ponatinib with blinatumomab combination therapies show rescue of LCK through phosphorylation of JAK-STAT5 signaling. Our findings can be used to explicate the significant role of TCR in combination therapy with biTEs. Future studies can extend into testing combination therapies with other kinase inhibitors with biTEs to report TKIs that will increase the efficacy of blinatumomab and propose potential therapeutic interactions that will improve ALL patient outcomes.