Cancer drugs that recruit antibodies from the body’s own immune system to help kill tumors have shown much promise in treating several types of cancer. But the tumors often return.

A new study from MIT reveals a way to combat these recurrent tumors with a drug that makes them more vulnerable to the antibody treatment. This drug, known as cyclophosphamide, is already approved by the 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,” says Michael Hemann, the Eisen and Chang Career Development Associate Professor of Biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study. “We can operate within the context of existing treatment regimens but hopefully achieve drastic improvement in the efficacy of those regimens.”

‘Tricking the immune system’

The MIT team 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.

“After you treat with cyclophosphamide you get this flux of macrophages into the bone marrow, and these macrophages are now active and very capable of consuming the targeted tumor cells,” Hemann says. “Essentially we are tricking the immune system to suddenly recognize an entity that it wouldn’t typically recognize and aggressively go after antibody-bound tumor cells.”

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. While 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 says.

The research was funded by the MIT Ludwig Center for Molecular Oncology, the Koch Institute Frontier Research Program through the Kathy and Curt Marble Cancer Research Fund, the Singapore-MIT Alliance for Research and Technology, the German Research Foundation, and the National Cancer Institute.\

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Abstract of Cell paper

• Low-dose chemotherapy sensitizes persisting tumor microenvironments to antibody therapy
• Chemotherapy promotes an acute cytokine response that boosts innate immune activity
• Tumor elimination depends on the timing of codosing chemo- and immunotherapy

Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNFα from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics.