New York, NY (Sept. 7, 2017)—Cancer immunotherapy drugs only work for a minority of patients, but a generic drug now used to increase blood flow may be able to improve those odds, a study by Columbia University Medical Center (CUMC) researchers suggests.
In mice with melanoma, the researchers found that the drug – called pentoxifylline – boosts the effectiveness of immune-checkpoint inhibitors, a type of immunotherapy now commonly used in the treatment of melanoma and other cancers.
The study was published today in the online edition of Cell.
Checkpoint-blockade immunotherapy drugs–the first drugs were approved in 2011–target proteins on tumor cells or cells of the immune system that prevent “killer” T cells from attacking cancer. These drugs have revolutionized cancer care but do not work for all patients. “In advanced melanoma, for example, the cure rate is only about 20 percent. That’s a remarkable improvement over previous therapies,” says study leader Sankar Ghosh, PhD, chair and Silverstein and Hutt Family Professor of Microbiology & Immunology. “But why doesn’t it work for the other 80 percent? There must be another mechanism that contributes to the suppression of the immune response.”
Dr. Ghosh and other cancer biologists suspected that a different type of T cell, known as regulatory T cells, or Tregs, may also suppress the immune system’s attack on cancer. Large numbers of these cells are found within several types of tumors. “One possible therapy would be to get rid of Tregs,” he said. “But Tregs are also needed to keep the immune system in check, and shutting down Tregs completely would unleash an attack against the body’s healthy cells and organs.”
This point is underscored by a related study, published today in Immunity, in which Dr. Ghosh and colleagues found that removing NF-kB from Tregs caused widespread and lethal autoimmunity in mice. However, a partial inhibition of NF-kB, achieved by removing only one specific NF-kB protein, called c-Rel, changed Treg function without causing widespread autoimmunity. In the Cell study Dr. Ghosh and colleagues showed that these c-Rel deficient Tregs were specifically crippled in their ability to protect cancer cells. As a result, when c-Rel is blocked, killer T cells mounted a more robust attack on cancer cells without causing autoimmunity.
Pentoxifylline is a drug that is used in patients to increase blood flow in the hands and feet of people with poor circulation, but it’s also known to inhibit the c-Rel protein. In the Cell study, the researchers demonstrated that pentoxifylline blocked Treg function and boosted the effectiveness of standard checkpoint-blockade immunotherapies. As a result, mice treated with both drugs showed significantly reduced melanoma tumor burden, compared with animals that received the standard therapy alone.
“The next step is to test this drug combination in human clinical trials,” Dr. Ghosh says. “If trials are successful, the use of c-Rel inhibitors could become a standard addition to immune checkpoint therapy for many types of cancer.”
The Cell paper is titled “NF-kB c-Rel is crucial for the regulatory T cell immune checkpoint in cancer.” The other contributors are Yenkel Grinberg-Bleyer (CUMC), Hyunju Oh (CUMC), Alexis Desrichard (Memorial Sloan Kettering Cancer Center, New York, NY), Dev Bhatt (CUMC), Rachel Caron (CUMC), Timothy Chan (Memorial Sloan Kettering Cancer Center), Roland Schmid (Technische Universität Munich, Munich, Germany), Matthew S. Hayden (CUMC), and Ulf Klein (CUMC). The study was funded by a grant from the National Institutes of Health (R01-AI068977).
The Immunity paper is titled “An NF-kB-dependent, lineage specific transcriptional program regulates Treg identity and function.” The other contributors are Hyunju Oh (CUMC), Yenkel Grinberg-Bleyer (CUMC), Will Liao (New York Genome Center, New York, NY), Dillon Maloney (New York Genome Center, New York, NY), Pingzhang Wang (CUMC), Zikai Wu (CUMC), Jiguang Wang (CUMC), Dev Bhatt (CUMC), Nicole Heise (CUMC), Roland Schmid (Technische Universität Munich, Munich, Germany), Matthew S. Hayden (CUMC), Ulf Klein (CUMC), and Raul Rabadan (CUMC). The study was funded by grants from the National Institutes of Health (R37-AI33443 and R01-AI068977).
There are no conflicts of interest to declare.
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