Drug-resistant tumors made vulnerable with cyclophosphamide

The drug cyclophosphamide may make recurrent tumors vulnerable again after they have developed resistance to cancer drugs that work by recruiting antibodies from the body's own immune system. Cyclophosphamide is already approved by the US Food and Drug Administration (FDA) to treat some cancers.

Antibody drugs work by marking tumor cells for destruction by the body's immune system, but they have little effect on tumor cells that hide out in the bone marrow. Cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment.

“We're not talking about the development of a new drug, we're talking about the altered use of an existing therapy,” said cosenior author Michael Hemann, PhD, of the Koch Institute for Integrative Cancer Research at Massachusetts Institute for Technology (MIT) in Cambridge. The study was published in Cell (2014; doi:10.1016/j.cell.2013.12.041). “We can operate within the context of existing treatment regimens but hopefully achieve drastic improvement in the efficacy of those regimens.”

Antibody-based cancer drugs are designed to bind to proteins found on the surfaces of tumor cells. Once the antibodies flag the tumor cells, immune cells called macrophages destroy them. Although many antibody drugs have already been approved to treat human cancers, little is known about the best ways to deploy them, and what drugs might boost their effects, Hemann explained.

The researchers first used mice to study an antibody drug called alemtuzumab, which is FDA-approved and in clinical trials for some forms of lymphoma. The drug successfully cleared most cancer cells, but some remained hidden in the bone marrow, which is a site of drug resistance in many types of cancer.

The study revealed that, within the bone marrow, alemtuzumab successfully binds to tumor cells, but macrophages do not attack the cells due to the presence of prostaglandins, which repress macrophage activity. Scientists believe that the bone marrow naturally produces prostaglandins to help protect the immune cells that are maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid in their own survival.

The MIT team then tested a variety of cancer drugs in combination with alemtuzumab and discovered that cyclophosphamide can rewire the bone marrow microenvironment to make it much more receptive to macrophages, allowing them to destroy the tumor cells hiding there. Following treatment with this combination of drugs, the mice survived, tumor-free, for the duration of the study—approximately 18 months.

Cyclophosphamide is often given to cancer patients as part of frontline chemotherapy. However, when cyclophosphamide was combined with alemtuzumab, it was effective at much lower doses than are typically given, which could help reduce side effects. Also, the timing of the drug delivery was critical: the antibody drug and cyclophosphamide must be given at the same time.

“Altering the regimens and the timing of these regimens is quite feasible,” Hemann said. “We're talking about more minor modifications in a trial that may have dramatic improvements in overall response.”

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