Researchers at the Baylor College of Medicine and their collaboration institutions have identified a combination therapy for treating triple-negative breast cancer (TNBC) that results in lasting tumor regression in an animal model of the disease.
On two fronts, the chemotherapy medication cyclophosphamide eliminated tumor cells, while on the other front, another medication inhibited tumor-associated cells called macrophages, which hinder the body''s immune response to the tumor. This two-front strategy effectively treated several highly aggressive TNBC primary tumors and metastasis. The study was published in the journal Cancer Research.
TNBC is an aggressive subtype of breast cancer, which has a significantly poorer prognosis than other breast cancer subtypes, according to co-corresponding authorDr. Jeffrey Rosen, Distinguished Service Professor of molecular and cellular biology at Baylor University.
In animal experiments, the team had previously shown that although cyclophosphamide removed the tumor initially, the disease recovered eventually. A closer examination of the tumor microenvironment revealed that the tumors that returned had generally a lot of macrophages.
We investigated the possibility that eliminating both the tumor cells and the macrophages would increase the chances of eliminating the tumor for a longer period of time, according to the first author of the paper and a student from the Baylorsgraduate school of biomedical sciences working together in the Rosen and Zhang laboratories. We eliminated macrophages with either a small molecule inhibitor or a monoclonal antibody towards CSF1R, a marker on these cells.
The tumors were treated with a combination of medications for several months. Eventually, they stopped treatment and followed up tumor progression in the treated animals.
Singh said that the results were really encouraging. Typically, a month after stopping the combination therapy, the tumors returned. We were delighted to see that the tumors did not return a month after stopping the combination therapy. In two animal models of TNBC, we observed a strong response.
These animals with a durable response were able to prevent new tumors from growing. We challenged them with fresh tumor cells, and 40% of them rejected them. This indicated that the animals had an immune system capable of combating new tumor growth. We also treated lung tumor metastasis with combination therapy, which found that it significantly reduced cancer growth.
With a sustainable response, Rosen and his colleagues investigated how the tumor microenvironment in the animals.
When we treated the tumors with one of the two drugs, which did not yield a durable response, immune B and T cells involved in the treatment did not enter the tumor mass, they remained in the periphery of the tumor mass, according to the co-author. Xiang H.F. Zhang, a fellow researcher at Baylor University, is the professor of molecular and cellular biology.
Both B and T cells were found in the tumor tumor mass after receiving combination therapy, suggesting that they were interacting to help with tumor elimination in a secure manner.
Researchers used this technique to determine if the macrophage signature they had observed in animal models was also present in TNBC from patients. In addition, tumors from patients with the worse symptoms also showed a significant number of macrophages, according to Rosen. This signature could help identify individuals who might be candidate for combination therapy.
The researchers are planning to conduct a clinical study to determine the value of their work in treating human TNBC.