Editors' ChoiceCancer

Patient, Heal Thyself

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Science Translational Medicine  06 Apr 2011:
Vol. 3, Issue 77, pp. 77ec47
DOI: 10.1126/scitranslmed.3002456

Harnessing the power of the patient’s immune system has recently emerged as a viable approach for treating cancer. Last April, the U.S. Food and Drug Administration (FDA) approved a therapeutic vaccine for the treatment of metastatic prostate cancer, and most recently the FDA approved ipilumimab, an antibody that targets CTLA-4 and boosts the ability of natural killer cells of the immune system to target melanoma cells. A study in the journal Science now reports a new way to boost other cells of the immune system to fight cancer. Beatty et al. demonstrate that a human antibody agonist of a surface receptor called CD40 in combination with the chemotherapeutic drug gemcitabine showed efficacy in patients with metastatic pancreatic ductal adenocarcinoma, a lethal cancer that is refractory to chemotherapy.

Using positron emission tomography­–compute tomography to monitor the tumors, the authors found that four out of 21 patients showed a partial response, 11 patients had stable disease, and four patients had progressive disease. CD40 activation is known to reverse immune suppression and harness the power of the T cell response to attack tumors. However, when the investigators looked at tumor biopsies from patients treated with the combination therapy who showed partial remission, they were surprised to see no T cells in the immune cell infiltrate in the shrunken tumors. To investigate this puzzling finding further, the authors turned to a genetically engineered mouse that develops pancreatic ductal carcinoma with very similar characteristics to the human cancer. The authors treated these genetically engineered mice with the combination therapy and obtained a 30% response rate. When they looked at the shrunken tumors from the mice that responded to treatment, they observed the same lack of infiltrating T cells as seen in the human tumors. However, they did see tumor-infiltrating macrophages bound to the CD40 antibody agonist in the stroma surrounding the tumor. Surmising that the macrophages were responsible for the antitumor effect, they depleted systemic macrophages using clodronate-encapsulated liposomes and found that the combination therapy no longer induced tumor shrinkage in the mice, suggesting that the macrophages were responsible for the antitumor response. This study shows an unexpected role for CD40 activation in macrophage-driven tumor killing and suggests a new strategy for combating not only pancreatic cancer but also other types of cancer.

G. L. Beatty et al., CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011). [Abstract] [Full Text]

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