Photo by Aaron Logan
Combining the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib with an anti-PD-L1 antibody can override resistance to ibrutinib, according to preclinical research.
Investigators found the combination of anti-PD-L1 and ibrutinib suppressed tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib.
The combination also proved effective against 2 solid tumor malignancies—triple-negative breast cancer and colon cancer.
Ronald Levy, MD, of the Stanford University School of Medicine in California, and his colleagues described this work in PNAS.
The team first studied A20, a B-cell lymphoma in BALB/c mice that is insensitive to ibrutinib treatment even though A20 cells express BTK.
A20 cells also express high levels of PD-L1, so it follows that some of the mice responded to anti-PD-L1 treatment alone. However, the response eventually diminished over time.
When the investigators administered ibrutinib along with anti-PD-L1, half of the mice were cured. The other half experienced delays in tumor growth and prolonged survival.
Dr Levy and his colleagues also assessed ibrutinib plus anti-PD-L1 in 2 solid tumor models. They chose triple-negative breast cancer and colon cancer, which do not express BTK and have low levels of the PD-L1 protein.
When ibrutinib and the PD-L1 antibody were given as single agents, neither had any effect on tumor growth. However, combination treatment reduced the size of the primary tumors, improved survival, and resulted in fewer metastases in both breast and colon cancer.
In the case of the colon cancer model, approximately 30% of the mice were cured. The investigators decided to test whether these mice had developed long-term immune memory from the treatment.
So the team re-exposed the mice to colon cancer cells at 90 days post-cure. After 7 days of tumor growth, all the mice cleared the tumor by day 17 without any additional dosing of the ibrutinib and anti-PD-L1 combination.
“These findings are very encouraging and support our pursuit of a clinical development strategy that combines ibrutinib with anti-PD-L1 antibodies or other checkpoint inhibitors to maximize the effect that both drugs could have in treating cancer,” said Darrin Beaupre, MD, PhD, of Pharmacyclics, the company developing ibrutinib, which contributed funding for this research.
“Based on what we’ve seen preclinically, we are optimistic that combinations such as these may help to produce new treatment paradigms for patients with cancer.”
The investigators did not draw any conclusions about the safety of anti-PD-L1 and ibrutinib in combination.
They did note that both agents have been well-tolerated when given alone, but additional study of the combination is needed to fully understand the appropriate dosing, timing, and sequencing of combination treatment.
Investigators are planning clinical studies testing ibrutinib in combination with the anti-PD-L1 immune checkpoint inhibitor MEDI4736 (in hematologic and solid tumor malignancies) and with the PD-1-blocking antibody nivolumab (in hematologic malignancies). Enrollment is expected to begin in the coming months.
