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Effective CpG Immunotherapy of Breast Carcinoma Prevents but Fails to Eradicate Established Brain Metastasis

Authors' Affiliations: Departments of ¹ Neurosurgery and ² Pediatrics, ³ Cancer Center, and ⁴ Stem Cell Institute, University of Minnesota Medical School, Minneapolis, Minnesota and ⁵ Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

Requests for reprints: John R. Ohlfest, Department of Pediatrics, University of Minnesota, 515 Delaware Street, SE, MMC 366, Minneapolis, MN 55455. Phone: 612-626-2491; Fax: 612-626-2490; E-mail: Ohlfe001{at}umn.edu.

Purpose: Breast cancer patients with brain metastasis have a dismal prognosis. We determined the ability of immunostimulatory CpG oligodeoxynucleotides (ODN) to treat or prevent brain metastasis in a mouse model.

Experimental Design: Mice bearing orthotopic breast carcinoma with or without concurrent i.c. tumors were treated by injections of CpG ODN at the primary tumor. Immunologic memory was tested by tumor rechallenge and immune responses were assessed by flow cytometry, delayed-type hypersensitivity, and CTL assays.

Results: Orthotopic tumors regressed in treated mice regardless of whether concurrent i.c. disease was present. In mice bearing only orthotopic tumors, CpG ODN rendered 50% tumor-free and they rejected tumor rechallenge in breast and brain. In mice with concurrent i.c. disease, there was no difference in brain tumor growth compared with saline controls, despite regression of the primary tumor. Flow cytometry revealed that treated mice that died from i.c. disease exhibited a significant increase in brain-infiltrating T and natural killer cells relative to saline controls. CTLs from these mice were able to kill tumor in vitro and extend survival of naive mice bearing less-established brain tumors by adoptive transfer.

Conclusions: The lack of survival benefit in mice with appreciable brain metastasis was not explained by a deficit in lymphocyte trafficking or function because CTLs from these mice killed tumor and inhibited microscopic brain metastasis by adoptive transfer. These results indicate that CpG ODN might be beneficial as a preventative adjuvant to initial therapy preceding brain metastasis or to inhibit progression of microscopic brain metastases.