Phase I clinical trial of a TGF-beta antisense-modified tumor cell vaccine in patients with advanced glioma.
We performed a phase I clinical trial in grade IV astrocytoma to assess the safety of a whole-cell vaccine comprising autologous tumor cells genetically modified by a transforming growth factor-beta2 (TGF-beta2) antisense vector. Blocking secretion of the immunosuppressive molecule TGF-beta in this manner should inhibit one of the major mechanisms by which tumor cells evade immune surveillance and should lead to clinically effective antitumor immunity. Six patients with progressive WHO grade IV astrocytoma were enrolled in the trial. Patients received 2-7 subcutaneous injections of 5 x 10(6)-2 x 10(7) autologous tumor cells per injection. TGF-beta2 secretion by the tumor cells used to vaccinate patients was inhibited by 53-98%. Treatment was well tolerated with only low-grade, transient treatment-related toxicities reported. Two patients had partial regressions and two had stable disease following therapy. The overall median survival was 68 weeks. Median survival of the responding patients was 78 weeks, compared to a historic value of 47 weeks for glioma patients treated conventionally. There were indications of humoral and cellular immunity induced by the vaccine. These findings support further clinical evaluation of vaccines comprised of TGF-beta antisense-modified tumor cells.
Fakhrai
H
H
Advanced Biotherapies, Inc., San Diego, CA, USA.
Mantil
J C
JC
Liu
L
L
Nicholson
G L
GL
Murphy-Satter
C S
CS
Ruppert
J
J
Shawler
D L
DL
D000328:Adult; D000917:Antibody Formation; D019496:Cancer Vaccines / Q000009:adverse effects / Q000235:genetics / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007271:Injections, Intradermal; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D053781:Transforming Growth Factor beta2 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; D016376:Oligonucleotides, Antisense; D053781:Transforming Growth Factor beta2