The use of certain traditional chemotherapy drugs may expand the number of tumors that respond to one of today’s most promising cancer therapies – immune checkpoint blockade. Researchers from the Massachusetts General Hospital (MGH) Center for Systems Biology report in the Feb. 16 issue of the journal Immunity that inducing the infiltration of cytotoxic T cells (CTLs) – immune cells that kill cancer cells and cells that are infected or in other ways damaged – into lung tumors sensitized otherwise unresponsive tumors to checkpoint blockade in animal models.
“Immune checkpoint blockade has revolutionized cancer therapy because it can durably control tumor progression, even in patients who fail to respond to other treatments,” says Mikael Pittet, PhD, of the MGH Center for Systems Biology, senior author of the Immunity paper. “But the drawback is that it only benefits a fraction of patients. We have found a way to make unresponsive lung tumors sensitive to checkpoint blockade immunotherapy and achieve long-lasting control of tumor growth in these animal models.”
One of the ways that tumors evade the immune system is by activating immune checkpoints – molecules that normally function to suppress the activity of CTLs. While clinical trials of drugs that block immune checkpoints have induced long-term control of several types of cancer, they have done so in only a minority of patients. The reason for this selective response is unclear, but evidence has suggested that patients whose tumors already contain CTLs are more likely to benefit.
The MGH-based team tested combinations of several FDA-approved chemotherapy drugs with the goal to find some that induce CTL infiltration within the tumors of several lung cancer mouse models. Only the combination of oxaliplatin and cyclophosphamide (Oxa-Cyc) did so. The researchers then showed that lung tumors in mice treated with Oxa-Cyc alone grew more slowly. Tumor control required not only CTL infiltration into tumors but also an increased activity of the innate immune system within the tumor microenvironment, which also was stimulated by Oxa-Cyc treatment. Furthermore, combining Oxa-Cyc treatment with immune checkpoint blockade durably controlled tumor growth in the lung cancer mouse models, which neither treatment was able to do alone. The investigators also identified other chemotherapy drugs that, when combined with immune checkpoint therapies in mice, could delay progression of other cancer types, including fibrosarcoma and colon cancer.
“The genetic mouse model of lung cancer used in this study is notoriously resistant to today’s cancer treatments, in contrast to many other models that are sensitive to several chemotherapy agents,” says Pittet, who is an associate professor of Radiology at Harvard Medical School. “We hope this model replicates treatment-resistant disease enough so that our findings can be translated to patients, but clinical trials are needed to examine whether that will be the case. Since the drugs shown to work in this study are all FDA-approved, the combination could be quickly tested in patients with lung cancer. We also plan to explore whether precision medicine approaches, which could identify drugs that best promote tumor infiltration by CTLs in a given patient, could extend the benefits of checkpoint blockade to even more patients.”
Christina Pfirschke, PhD, and PhD student Camilla Engblom of the MGH Center for Systems Biology, are co-lead authors of the Immunity paper. Additional co-authors include Ralph Weissleder, MD, PhD, director of the MGH Center for Systems Biology; Richard O. Hynes, PhD, Massachusetts Institute of Technology; Gordon J. Freeman, PhD, Dana-Farber Cancer Institute; and Guido Kroemer, MD, PhD, PU-PH, and Laurence Zitvogel, MD, PhD, Gustave Roussy Cancer Campus, Villejuif, France. Support for the study includes a grant from the Samana Cay MGH Research Scholar Fund and National Institutes of Health grants P50-CA86355, R01-AI084880, U54-CA126515, 5U54CA163125 and 5U54-CA163109.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $800 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."
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