Pharmacyclics, Inc. PCYC today highlighted findings from a pre-clinical study published in the
Proceedings of the National Academy of Sciences
(www.pnas.org/cgi/doi/10.1073/pnas.1500712112) that showed when ibrutinib
(IMBRUVICA^®) was combined with an anti-PD-L1 antibody (a checkpoint
inhibitor), suppression of tumor growth was enhanced suggesting a greater
response might be achieved when treating certain hematologic cancers and solid
tumors with the combination. IMBRUVICA is jointly developed and commercialized
by Pharmacyclics and Janssen Biotech, Inc.
The paper's senior author, Ronald Levy, M.D., a professor of medicine and
director of the lymphoma program at the Stanford University School of
Medicine, and colleagues found the combination of an anti-PD-L1 antibody and
ibrutinib resulted in suppression of tumor growth and extension of survival in
a mouse model of lymphoma. The study found while some of the mice responded to
anti-PD-L1 treatment alone, the response eventually diminished over time. When
ibrutinib was added to anti-PD-L1 treatment, half of the mice were cured and
the other half experienced delays of tumor growth and prolonged survival.
The researchers also chose two solid tumor models to investigate the novel
combination – triple negative breast cancer and colon cancer, which do not
express BTK (Bruton's tyrosine kinase) 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, the combination reduced the
size of the primary tumors, improved survival and resulted in fewer metastases
in both breast and colon cancer. Specifically, in the case of the colon cancer
tumor model, approximately 30% of the mice were cured.
Most importantly, the researchers tested whether the mice cured from colon
cancer had developed long-term immune memory, specific memory T cells, from
the novel combination. These mice were re-exposed to colon cancer cells 90
days post cure and after seven days of tumor growth, all the mice cleared the
tumor by day 17 without any additional dosing of the ibrutinib and PD-L1
combination.
Programmed death-ligand (PD-L1) is a protein that may suppress the ability of
the immune system to fight diseases. In certain cancers, PD-L1 may play a role
in inhibiting the ability of T cells (necessary to help the body fight
disease) to function properly, which results in the proliferation of tumors in
the human body. Anti-PD-L1 antibody therapies have been shown to block the
negative effect that PD-L1 can have on T cells, allowing certain cancers to be
successfully treated. Recent pre-clinical studies have also demonstrated that
ibrutinib, which has been shown to be effective in treating B-cell mediated
cancers, can also inhibit interleukin-2-inducible T-cell kinase (ITK), an
enzyme important in regulating T-cell effector function. This activity may be
relevant to the mechanism by which ibrutinib enhances the efficacy of check
point inhibitors.
"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, M.D., Ph.D., Head of Early
Development and Immunotherapy at Pharmacyclics. "Based on what we've seen
pre-clinically, we are optimistic that combinations such as these may help to
produce new treatment paradigms for patients with cancer."
While no conclusions about the safety of this combination were drawn, the
authors noted while ibrutinib and anti-PD-L1 antibodies have each been well
tolerated as single agents, additional study of the combination of these two
agents is necessary to fully understand the appropriate dosing, timing and
sequencing of combination treatment.
IMBRUVICA will be evaluated with AstraZeneca's investigational anti-PD-L1
immune checkpoint inhibitor, MEDI4736 in patients with several hematologic and
solid tumor cancers, all of which are investigational uses for both compounds.
IMBRUVICA also will be studied with Bristol-Myers Squibb's human programmed
death receptor-1 (PD-1) blocking antibody OPDIVO^® (nivolumab) in several
hematologic cancers. These clinical studies are expected to begin enrollment
in the coming months.
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