Eradication of established intracranial rat gliomas by transforming growth factor beta antisense gene therapy.
Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor beta (TGF-beta). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-beta expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-beta expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-beta antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-beta expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-beta antisense gene therapy for TGF-beta-expressing tumors.
Fakhrai
H
H
Sidney Kimmel Cancer Center, San Deigo, CA 92121, USA.
Dorigo
O
O
Shawler
D L
DL
Lin
H
H
Mercola
D
D
Black
K L
KL
Royston
I
I
Sobol
R E
RE
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D016373:DNA, Antisense / Q000008:administration & dosage / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D018316:Gliosarcoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000096:biosynthesis; D008214:Lymphocytes / Q000276:immunology; D010957:Plasmids; D051381:Rats; D011916:Rats, Inbred F344; D012190:Retroviridae; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics*
D016373:DNA, Antisense; D007376:Interleukin-2; D016212:Transforming Growth Factor beta