Ibrutinib Boosts Anti-Tumor Activity of Anti-PD-L1 Antibody

Adding an immune therapy to a targeted drug resulted in responses in lymphoma and several solid tumor mouse models, including breast cancer, that were initially non-responsive to the targeted agent alone.

The combination of ibrutinib, (an oral inhibitor of Bruton’s tyrosine kinase (BTK), and an antibody against the programmed death-ligand 1 (anti-PD-L1, an immune checkpoint inhibitor), suppressed tumor growth in mouse models of lymphoma that are inherently insensitive to ibrutinib. The results are published in the Proceedings of the National Academy of Sciences.  

Ibrutinib (Imbruvica, Pharmacyclics and Janssen Biotech) is currently approved by the Food and Drug Administration (FDA) for the treatment of a type of chronic lymphocytic leukemia (CLL) that carries a deletion in chromosome 17 (17p deletion), that historically has had a poor response to standard therapy. Ibrutinib is also approved for mantle cell lymphoma for those patients who have received at least one prior therapy.

Currently, two immune checkpoint inhibitor antibodies are approved by the FDA. Ipiliumumab, an anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, is approved for treatment of metastatic melanoma. Additionally, pembrolizumab (Keytruda, Merck), an anti-PD-1 antibody, is also approved for metastatic melanoma.

Two additional immune checkpoint inhibitors, MPDL3280A (Roche), an anti-PD-L1 antibody, and nivolumab (Opdivo, Bristol-Myers Squibb), an anti-PD-1 antibody are also in advanced stages of development. Nivolumab is currently being tested in melanoma, lung, and renal cell carcinoma. MPDL3280A is in late-stage development for lung and bladder cancer.

Thus far, immune checkpoint inhibitors have shown robust responses and long-term remissions in a fraction of patients. Researchers are now trying combinations, with other immunotherapies and targeted therapies.

In the current study, Ronald Levy, MD, of the division of oncology and the department of Medicine at Stanford University, and colleagues, used a mouse model of a B-cell lymphoma that expressed BTK, but insensitive to ibrutinib. A cell line derived from the mouse model expressed high levels of PD-L1, but was insensitive to an anti-PD-L1 antibody treatment of the mice, which resulted in delayed tumor growth and a modest increase in overall survival. Combining ibrutinib with the immune therapy resulted in the cure of half of the mice treated and a delay in tumor progression, and improvement in survival in the rest of the mice. The results were confirmed using a second myeloma, ibrutinib-insensitive tumor model.

Analyses of the T-cell responses in the mice led the authors to conclude that, “ibrutinib was able to convert a weak antitumor T-cell immune response induced by anti–PD-L1 antibody into a powerful one, in this lymphoma model that was insensitive to ibrutinib as a single therapy.”

A similar response to the combined therapy was also seen in a triple-negative breast cancer and colon cancer cell lines--both of which have low PD-1 expression. While each drug on its own did not have any effect on these mouse tumors, mice treated with the combination resulted in shrinking of the primary tumors and increased survival. Thirty percent of the mice with colon cancer were cured with the combination therapy.

When the mice, cured of their colorectal tumors with the combination therapy, were re-challenged with the same colorectal tumor cells, the mice were resistant. But the cured colorectal tumor mice re-challenged with a different tumor type were sensitive to the new tumor cells. “This result indicates that the mice cured by the combined therapy had long-term memory to tumor antigens expressed specifically in the [colorectal] tumor,” concluded the authors.

In their discussion, the authors highlight that caution needs to be taken when combining an immunotherapy with another drug, as unexpected toxicities may result. For combination immunotherapy clinical trials, the dose and dosing schedule are important to consider.

The current study presents evidence that ibrutinib may play a role as an enhancer of T-cell directed therapies. Besides targeting BTK, ibrutinib also inhibits ITK (interleukin-2-inducible T-cell kinase), an enzyme important for the survival of a subset of T-cells which could result in the drug’s immunomodulatory effects.