Phase I study of immunotherapy of hepatic metastases of colorectal carcinoma by direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7

We have completed a phase I study to test feasibility and toxicity of immunotherapy of hepatic metastases from colorectal carcinoma by direct 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 response of the injected lesion, as well as evaluation of possible distant response. Under ultrasonographic guidance the hepatic lesions were injected with Allovectin-7, a liposomal vector containing the combination the HLA-B7 gene with beta(2)-microglabulin formulated with the lipid DMRIE-DOPE. Eligible patients were injected on two schedules. On the first schedule patients received an injection day 1 and the injected lesion was biopsied to determine transfection every 2 weeks for 8 weeks. Doses were escalated from 10 mu g to 50 mu g to 250 mu g with three patients treated at each level. The second schedule included multiple 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 total of 15 patients have completed treatment. The plasmid DNA was defected in 14 of 15 patients (93%) by PCR. In five of 15 patients (33%) mRNA-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. There has been no serious toxicity directly attributable to allovectin-7. Our results suggest that liposomal gene transfer by direct injection is feasible-and non-toxic. Further, studies will be necessary in order to establish the therappeutic efficacy.