May 1, 2019, New York—A research team led by Ludwig Harvard investigator Rakesh Jain at Massachusetts General Hospital and Robert Langer of MIT has found that combining a specialized version of an antihypertension drug with immune checkpoint blockers could increase the effectiveness of cancer immunotherapies. They report in a paper posted online in the Proceedings of the National Academy of Sciences on April 30 that the combination treatment significantly improved tumor response and survival in mouse models of breast cancer, one of several types of solid tumor that have resisted immunotherapy.
Most cancers are not responsive to immunotherapies. The current study supports a growing body of evidence suggesting resistance to immunotherapy is often caused by multiple mechanisms that suppress or exclude immune cells from the tumor microenvironment. More important, the study finds that such immunosuppression may be reversed by “reprogramming” that microenvironment using drugs already in clinical use for other indications known as angiotensin receptor blockers.
Cells called cancer-associated fibroblasts (CAFs) are among the factors known to inhibit antitumor immune responses in several ways, which include barring entry of T cells and promoting acidity and hypoxia—both of which promote the activity of the regulatory T cells that suppress the immune response and increase the expression of immune checkpoint proteins. Immunosuppressive CAFs also secrete factors that increase regulatory T cell activity while preventing the entry of antitumor CD8 T cells.
Other forms of CAFs can enhance the immune response, raising the possibility of reprograming the cells from immunosuppressive to immunostimulatory states. While blood pressure drugs known as angiotensin receptor blockers (ARBs) can reprogram CAFs from an active to a quiescent state, their ability to change the cells’ immunomodulatory functions in breast cancer was unknown.
The investigators developed a way to deliver ARBs only to the tumor microenvironment, screening for that purpose more than 1,000 polymers that would break down in the low-pH environment around tumors but remain stable at the higher pH levels of healthy tissue. They then linked an ARB to the most pH-selective of these polymers, creating a tumor-microenvironment-activated ARB (TMA-ARB).
Experiments in three different mouse models of breast cancer revealed, among other things, that TMA-ARBs induce changes in gene expression indicating reversal of immunosuppression and the activation of immune-stimulating pathways in the tumor microenvironment. Combining TMA-ARBs with immune checkpoint blockers results in greater stimulation of antitumor immune responses than either therapy alone. Such treatment significantly improved treatment responses in models of primary breast cancer and extended survival in models of metastatic cancers.
“Although the new TMA-ARB we developed is not yet clinically available, there are many ARBs in clinical use for hypertension,” says Jain, who is also director of the Steele Laboratories at Massachusetts General Hospital and the A.W. Cook Professor of Radiation Oncology at Harvard Medical School. “So it is possible that some can be repurposed in combination with immune checkpoint blockers for cancer therapy. In fact, my clinical collaborators are testing this concept in a multi-institutional randomized clinical trial in pancreatic cancer patients.” More about that trial can be found at ClinicalTrials.gov (Identifier: NCT03563248).
The MGH release from which this summary is derived can be found here.
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