PDL1 CHECKPOINT BLOCKADE SYNERGIZES WITH NILOTINIB BUT NOT DASATINIB TO PREVENT LEUKEMIA RELAPSE

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Tyrosine Kinase Inhibitors (TKIs) like dasatinib and nilotinib are crucial for treating BCR-ABL+ leukemias.
• Previous research indicated that combining nilotinib with anti-PD-L1 blockade effectively reduces leukemia relapse.
• Dasatinib, commonly used for B-ALL, also inhibits SRC-family kinases, potentially affecting its efficacy with immunotherapy.

Purpose of the Study:

• To evaluate the impact of nilotinib versus dasatinib on anti-leukemia immune responses.
• To determine if dasatinib's SRC-family kinase inhibition affects its combination therapy efficacy with anti-PD-L1 blockade.

Main Methods:

• In-vitro assessment of T cell proliferation inhibition by TKIs.
• In-vivo evaluation of T cell function and expansion using a model antigen and adjuvant.
• Comparison of leukemic blast reduction and relapse prevention with TKI and anti-PD-L1 combinations.

Main Results:

• Dasatinib, unlike nilotinib, inhibited T cell proliferation in-vitro at high doses.
• Neither TKI significantly altered T cell function or expansion in-vivo.
• Both TKIs equally reduced leukemic blasts after 5 days; however, only nilotinib plus anti-PD-L1 prevented relapse weeks later.

Conclusions:

• Dasatinib negatively impacts protective anti-leukemia T cell responses.
• Nilotinib combined with anti-PD-L1 blockade is more effective in preventing leukemia relapse compared to dasatinib combinations.