Researchers at Massachusetts General Hospital (MGH) and the Massachusetts Institute of Technology (MIT) recently discovered that the combination of an antihypertension drug and immune checkpoint inhibitors can increase the success of cancer immunotherapies. Their report was published in PNAS, and showed that this specialized combination therapy substantially increased tumor response and survival in mouse models of breast cancer.
Breast cancer tumors are notorious for resisting immunotherapy treatments. As Vikash P. Chauhan, Ph.D., co-lead author of the study, said, “Although immunotherapy has revolutionized the treatment of some types of cancer, more than 80 percent of cancer patients have disease that will not respond to these therapies alone.”
Researchers are still trying to determine exactly why some tumors are unresponsive. This team discovered one potential answer to this question. According to Chauhan, “The tumor microenvironment can block the entry of T lymphocytes and hinder their function, causing immunotherapies to fail. We show that this type of immunosuppression may be reversed by reprogramming the microenvironment with drugs called angiotensin receptor blockers.”
Cells known as cancer-associated fibroblasts (CAFs) are commonly responsible for preventing antitumor immune responses and other kinds of cancer treatments in many ways. They can cause a buildup of the extracellular matrix made of collagen fibers and hyaluronan that literally block T cells from entering, compress blood vessels, and cause environment stresses like low pH and hypoxia. These factors both incite regulatory T cell activity that prevent immune response. CAFS can also release factors that increase regulatory T cell activity and prevent antitumor CD8 T cells from entering.
But certain forms of CAFs can also bolster immune response, which increases the possibility of changing the cells from immunosuppressive to immunostimulatory states. Angiotensin receptor blockers have the ability to turn CAFs from active to quiescent, but whether they can change the cells’ immunomodulatory functions is still unknown. The effects of the ARBs, including a decrease in blood pressure, could also present safety issues.
In this trial, the researchers came up with a way to administer ARBs only to the tumor microenvironment. They began by creating a library of over 1,000 polymers that were thought to be sensitive to environmental pH, and then found the ones that broke down in the acidic environment around tumors, but stayed stable at the higher pH levels in healthy tissue. Linking an ARB to the most pH-selective of these polymers, the team developed a tumor-microenvironment-activated ARM (TMA-ARB).
The experiments used three different mouse models of breast cancer tumors. The studies showed that TMA-ARBs accumulated in tumors in levels seven times greater than free ARBs and release ARBs into the tumor. Blood pressure was also affected very little. TMA-ARBs were also found to normalize the tumor microenvironment, which decreased the expression of collagen, solid stress, and blood vessel compression more than free ARBs.
TME-ARBs created changes in gene expression which suggested a reversal of immunosuppression and activate immunosupportive pathways in the tumor microenvironment. A combination of TMA-ARBs enhanced the efficacy of immune checkpoint inhibitors, which in turn created substantial treatment response increases and extended survival in mouse models with metastatic breast cancer.
The TMA-ARB drug is not yet available to the public, co-senior author Rakesh K Jain, Ph.D. believes that ARBs already in use for hypertension could be repurposed to use for cancer therapy, especially in combination with checkpoint inhibitor drugs.