Credit: Linda Bartlett
Adding the alkylating agent cyclophosphamide to treatment with a monoclonal antibody (mAb) can overcome drug resistance in mice with acute lymphoblastic leukemia (ALL), researchers have reported in Cell.
mAbs such as rituximab and alemtuzumab are designed to bind to proteins found on the surfaces of tumor cells.
Once the mAbs flag the tumor cells, macrophages destroy them. But the drugs have little effect on tumor cells that hide out in the bone marrow.
Experiments in mice with B-cell ALL revealed that cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment with a mAb.
Finding hidden ALL cells
Michael Hemann, PhD, of MIT’s Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, and his colleagues began this research by administering alemtuzumab to the mice.
The drug successfully cleared most ALL cells, but some remained hidden in the bone marrow, which has been identified as a site of drug resistance in many cancers.
The researchers found that, within the bone marrow, alemtuzumab successfully binds to ALL cells. But macrophages do not attack the cells due to the presence of lipid compounds called prostaglandins, which repress macrophage activity.
Scientists believe the bone marrow naturally produces prostaglandins to help protect the immune cells maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid their own survival.
The finding is an important contribution to scientists’ understanding of how mAbs act against ALL, according to Ravi Majeti, MD, PhD, of Stanford University in California, who was not involved in this research.
“There clearly has been a lack of understanding about why antibody therapies have been relatively unsuccessful as monotherapies,” Dr Majeti said.
Tricking the immune system
Dr Hemann and his colleagues then tested a variety of anticancer drugs in combination with alemtuzumab. And they 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,” Dr Hemann said.
“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.”
Following treatment with this combination, the mice survived and remained free of ALL for the duration of the study, which was about 18 months.
However, the researchers found that timing of drug delivery was critical. Alemtuzumab and cyclophosphamide must be administered together so that cyclophosphamide can create the right type of environment for macrophages to become activated in the bone marrow.
The team also obtained good results by combining cyclophosphamide with rituximab.
They now plan to test cyclophosphamide with other mAbs and begin testing the alemtuzumab-cyclophosphamide combination in patients.
