PUBLICATIONS
Anti-tumor Responses in Dogs with Spontaneous Astrocytoma and Papillary Meningioma Treated by Immunotherapy
G. Elizabeth Pluhar3, Wei Chen2, Patrick T. Grogan2, Charlie Seiler3, Mike Olin2, Cathy Carlson4, Karen A. SantaCruz5, Maria G. Castro6, Pedro R. Lowenstein6, Stephen Haines1, Matthew A. Hunt1, John R. Ohlfest1,2
1 Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455.
2 Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455
3 Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, MN 55108
4 Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN 55108
5 Department of Lab Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455
6 Gene Therapeutics Research Institute, Cedars-Sinai Medical Center, Department of Medicine and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los, Los Angeles, California 90048 Background: WHO grade II-III astrocytoma and meningioma are often incurable with standard therapies. One major hurdle in developing adjuvant therapy for these tumor types is the paucity of biologically relevant animal models. Pet dogs spontaneously develop these tumors that are amenable to surgical resection plus adjuvant therapy, similar to human treatments. Although canine and human tumors exhibit many histological similarities, the disease progression is much more rapid in dogs. Therefore these dogs represent an attractive model to test experimental therapies. We have initiated a canine brain tumor clinical trials program and have treated several dogs including one with gemistocytic astrocytoma and two with papillary meningioma.
Methods: The dog with astrocytoma was treated by surgical debulking, intracavitary interferon gene transfer, and vaccination with glioma cell lysate mixed with an adjuvant, CpG oligodeoxynucleotides (ODN). Dogs with papillary meningioma were treated by surgical debulking and tumor lysate/CpG ODN vaccination.
Results: In the astrocytoma case, vaccination induced a tumor-reactive IgG response that has persisted for over 250 days, consistent with no evidence of tumor documented by MRI. Repeated vaccinations induced temporary blindness and left-sided hemiparesis suggestive of inflammation in the tumor-infiltrated right hemisphere. Residual tumor volume decreased by over 50% in both dogs with papillary meningioma. Tumor regression correlated with complete resolution of neurological symptoms and improved overall health. An apparent delayed type hypersensitivity reaction that increased in severity following each vaccination at the injection sites occurred in one dog. Lymphopenia and mild elevation in liver enzymes occurred after lysate/CpG vaccinations in all cases. In several dogs vaccination induced an IgG response against multiple tumor antigens, yet only a fraction of these were sustained as a memory response. Conclusions: Tumor lysate/CpG vaccination induces clinically relevant anti-tumor immunity in dogs with spontaneous tumors that are often incurable and warrants testing in patients with similar histology.
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