A phase I clinical trial of interferon-beta gene therapy for high-grade glioma: novel findings from gene expression profiling and autopsy.
BACKGROUND
High-grade gliomas are highly lethal neoplasms representing approximately 20% of all intracranial tumors. Cationic liposome-mediated interferon-beta (IFN-beta) gene transfer has been found to induce regression of experimental glioma. We have previously performed a pilot clinical trial to evaluate the safety and effectiveness of this IFN-beta gene therapy in five patients with high-grade glioma. Two patients showed more than 50% reduction while others had stable disease 10 weeks after treatment initiation.


METHODS
To identify alterations in gene expression in brain tumors 2 weeks after the gene therapy trial, we used a microarray technology and Gene Ontology analysis. The results were validated by patients' clinical course and findings of histology and autopsy.


CONCLUSIONS
Using hierarchical clustering and principal component analysis, five series of gene therapy trials were classified according to the response to IFN-beta gene therapy. Significant changes in gene expression related to immunoresponse and apoptosis were observed. Moreover, novel patterns of altered gene expression, such as inhibition of neovascularization, were identified, suggesting the involvement of pathways reported previously as not involved. Autopsy and histological examinations revealed dramatic changes in the tumor tissues after therapy in all patients. Many tumor cells showed necrotic changes, and immunohistochemistry identified numerous CD8-positive lymphocytes and macrophages infiltrating the tumor and surrounding tissues; these were probably the effects of therapy. Simultaneously, CD34-immunoreactive vessels were notably decreased in the vector-injected brain. This study facilitates the understanding of the antitumor mechanism and helps identify candidate target molecules for new approaches. However, additional clinical trials are warranted.
Wakabayashi
Toshihiko
T
Center for Genetic and Regenerative Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
Natsume
Atsushi
A
Hashizume
Yoshio
Y
Fujii
Masazumi
M
Mizuno
Masaaki
M
Yoshida
Jun
J
D000328:Adult; D017209:Apoptosis / Q000235:genetics; D001344:Autopsy; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007109:Immunity / Q000235:genetics; D016899:Interferon-beta / Q000235:genetics*; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016896:Treatment Outcome
D008081:Liposomes; D016899:Interferon-beta