The dual Src/ABL inhibitors dasatinib & potaninib inhibited blinatumomab induced T-cell proliferation in vitro at nanomolar concentrations.
Potential immunomodulatory effects of targeted therapies should be taken into consideration before they are combined with immunotherapies.
Blinatumomab is currently approved for use as a single agent in relapsed and refractory Acute Lymphoblastic Leukemia. Cytotoxicity is mediated via signaling through the T-cell Receptor (TCR). There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia Chromosome positive ALL (Ph+ALL). However, some second and third generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual ABL/Src inhibitors with blinatumomab in vitro from both healthy donor samples as well as in primary samples from patients with Ph+ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells, as well as enhanced production of IFN-gamma. The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation nor IFN-gamma production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-gamma production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples as well as samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies highlighting the importance of maintaining T-cell function with targeted therapies.