NEW YORK – Inflammation is a hallmark of solid tumors, and chronic inflammation is a key regulator of T cell biology and therapeutic response in cancer. Bruton’s tyrosine kinase (BTK), a target in blood cancers for BTK inhibitors such as ibrutinib (Imbruvica), also poses a promising means to modulate humoral immunity and quiet a tumorigenic environment in solid tumors.
At the first International Cancer Immunotherapy Conference, Lisa Coussens, Ph.D., professor and chair of the department of cell, developmental, and cancer biology at Oregon Health Sciences University and associate director of basic research at Knight Cancer Institute, Portland (Ore.), provided a background and summarized how she and collaborators are working to limit B cell activity through inhibiting BTK.
BTK is an enzyme that plays a role both in B cell maturation and mast cell activation. Dr. Coussens, noting the importance of humoral immunity in many cancers, cited the work of Karin de Visser, Ph.D., among other researchers, who has found that circulating immune complexes can be angiogenic and tumorigenic.
In particular, the T helper-2 pathway (Th2), to a much greater extent than the Th1 pathway, can be proangiogenic, profibrotic, and immune suppressive. In cancer, when this pathway is unregulated, it “lets a tumor grow and be bad,” said Dr. Coussens.
Dr. Coussens said that Dr. de Visser’s work asks the key question: “If we depleted B cells, could we abate this pathway?”
The mechanism by which T cells are suppressed, she said, is tissue specific rather than oncogene specific. Mouse models of mammary adenocarcinoma, squamous cell carcinoma, and non–small cell lung adenocarcinoma have helped elaborate the importance of blocking the Th2 phenotype or promoting the Th1 pathway, resulting in CD8+ T cell mobilization. When the balance shifts to a Th1-predominant milieu, said Dr. Coussens, the host environment becomes angiostatic, immunostimulatory, and ultimately antitumorigenic.
In humans with chronic lymphocytic leukemia, the BTK pathway is activated in B cells and in the myeloid compartment. BTK inhibitors such as ibrutinib are currently in use for lymphomas and chronic lymphocytic leukemia.
Though BTK positive cells are also seen in pancreatic cancer. Dr. Coussens said that pancreatic cancer had been considered largely immunologically inert until recently, when researchers have begun to pay more attention to humoral immunity in the disease. However, asked Dr. Coussens, “Does the humorally mediated signature appear as a tractable target?”
To help answer the question, Dr. Coussens and her collaborators have recently shown that BTK inhibition improves response to gemcitabine in pancreatic cancer in a mouse model. Mice with an induced pancreatic tumor received the BTK inhibitor (BTKi) termed ACP-196 alone, gemcitabine alone, both, or neither. After 28 days, the combination group had significantly smaller tumor size than any other group.
Decreased desmoplasia was seen in tumor pathology when gemcitabine was combined with another BTKi, ibrutinib, said Dr. Coussens. An early dosing strategy, she said, shows that BTKi can also be effective as monotherapy when begun early enough in both tumor models studied.
Current clinical trials are underway investigating BTK inhibition in combination with conventional chemotherapy for pancreatic duct adenocarcinoma, as well as for head and neck squamous cell carcinoma.
Potential mechanisms for the promising efficacy of BTK inhibition in solid tumors include regulation of macrophage adhesion to the extracellular matrix, with suppressed adhesion to VCAM-1, and suppressed integrin activation. “Tumors are quite likely dying as a consequence of failure to adhere outside of the tumor environment,” said Dr. Coussens.
Dr. Coussens reported being on the advisory boards of Pharmacyclics Inc (the manufacturer of ibrutinib); AstraZeneca; Cellgene; and Five Prime. She receives research support from multiple pharmaceutical companies.
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