Editors' ChoiceCancer and Immunology

Dynamic Duo: Cancer Drugs and the Immune System

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Science Translational Medicine  23 Dec 2009:
Vol. 1, Issue 12, pp. 12ec44
DOI: 10.1126/scitranslmed.3000733

When the protagonist of Margaret Edson’s Pulitzer Prize–winning play Wit is diagnosed with stage 4 ovarian cancer, she wryly remarks, "There is no stage 5." This simple statement highlights the unmet medical need represented by this intractable form of cancer. The successful treatment of any cancer depends on the ability of drugs to kill all of the patient's cancer cells, a standard that is largely unmet at the usual doses of anticancer therapeutics. One approach to the comprehensive killing of cancer cells is to boost the immune system so that it finishes the job started by the drug. Now, Alagkiozidis et al. show in a preclinical mouse model of ovarian cancer that treatment with a combination of the drug Doxil and the cytokine interleukin-18 (IL-18) inhibits tumor growth and promotes tumor regression better than either therapy alone.

Cancer cells can thwart immune attack by decreasing the number of molecules that decorate their surfaces and that normally mediate recognition by immune cells. Like many cytotoxic cancer drugs, Doxil kills cells by inserting itself into the DNA and blocking its replication. But Doxil has an added benefit: It also modulates the host’s immune system by augmenting its ability to stimulate tumor cell death. The authors used an ovarian cancer mouse model (ID8) that mimics the human disease so as to characterize cancer cells that survived Doxil treatment and found that these tumor cells were rendered sensitive to killing by cytotoxic T cells in vitro. The authors then made use of the immune-stimulatory effects of Doxil by treating mice bearing ID8 tumors with both Doxil and IL-18. This cytokine was shown recently to stimulate certain types of immune cells, to protect mice from tumor challenge, and to be well-tolerated in phase I safety trials in patients with solid tumors.

In this study, the combination therapy decreased tumor growth more than either therapy alone and yielded 6-month overall survival in 22% of mice as compared with 0% of mice that received only one of the treatments. Further, the tumor-bearing mice that survived for 6 months were effectively protected from re-challenge with ID8 tumor cells. These findings suggest that the anticancer effects of Doxil may be enhanced when supplemented with immunotherapy.

Alagkiozidis et al., Increased immunogenicity of surviving tumor cells enables cooperation between liposomal doxorubicin and IL-18. J. Transl. Med. 10 December 2009 (10.1186/1479-5876-7-104). [Full Text]

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