PHASE-I STUDY OF IMMUNOTHERAPY OF HEPATIC METASTASES OF COLORECTAL-CARCINOMA BY DIRECT GENE-TRANSFER OF AN ALLOGENEIC HISTOCOMPATIBILITY ANTIGEN, HLA-B7
J. Rubin et al., PHASE-I STUDY OF IMMUNOTHERAPY OF HEPATIC METASTASES OF COLORECTAL-CARCINOMA BY DIRECT GENE-TRANSFER OF AN ALLOGENEIC HISTOCOMPATIBILITY ANTIGEN, HLA-B7, Gene therapy, 4(5), 1997, pp. 419-425
We have completed a phase I study to test feasibility and toxicity of
immunotherapy of hepatic metastases from colorectal carcinoma by direc
t gene transfer of HLA-B7, a MHC class I gene. Eligible patients were
HLA-B7 negative, immunocompetent by PHA lymphocyte stimulation and had
least two measurable hepatic lesions on CT scan for measurement of re
sponse of the injected lesion, as well as evaluation of possible dista
nt response. Under ultrasonographic guidance the hepatic lesions were
injected with Allovectin-7, a liposomal vector containing the combinat
ion the HLA-B7 gene with beta(2)-microglabulin formulated with the lip
id DMRIE-DOPE. Eligible patients were injected on two schedules. On th
e first schedule patients received an injection day 1 and the injected
lesion was biopsied to determine transfection every 2 weeks for 8 wee
ks. Doses were escalated from 10 mu g to 50 mu g to 250 mu g with thre
e patients treated at each level. The second schedule included multipl
e injections of 10 mu g. Three patients received injections on days 1
and 15. Three patients received injections on days 1, 15 and 29. A tot
al of 15 patients have completed treatment. The plasmid DNA was defect
ed in 14 of 15 patients (93%) by PCR. In five of 15 patients (33%) mRN
A-was also detected. The HLA-B7 protein was defected in five of eight
patients (63%) by immunohistochemistry and in seven of 14 patients (50
%) tested by fluorescence activated cell sorting (FACS) analysis. Ther
e has been no serious toxicity directly attributable to allovectin-7.
Our results suggest that liposomal gene transfer by direct injection i
s feasible-and non-toxic. Further, studies will be necessary in order
to establish the therappeutic efficacy.