The utilization of catheter-based gene delivery in vivo provided a model system for the 
introduction of recombinant gene-specific sites in vivo. Early studies focused on the 
demonstration that specific reporter genes could be expressed in vivo (13,14). Subsequent 
studies were designed to determine whether specific biologic responses could be induced 
at sites of recombinant gene transfer. To address this question, a highly immunogenic 
molecule, a foreign major histocompatibility complex (MHC), was used to elicit an immune 
response in the iliofemoral artery using a porcine model.' The human HLA-B7 gene was 
introduced using direct gene transfer with a retroviral vector or DNA lipid complex (12). 
With either delivery system, expression of the recombinant HLA-B7 gene product could be 
demonstrated at specific sites within the vessel wall. More importantly, the expression of 
this foreign histocompatibility antigen induced an immunologic response at the sites of 
genetic modification. This response included a granulomatous mononuclear cell infiltrate 
beginning 10 days after introduction of the recombinant gene. This response resolved by 75 
days after gene transfer; however, a specific cytolytic T cell response against the HLA-B7 
molecule was persistent. This study demonstrated that a specific immunologic response 
could be induced by the introduction of a foreign recombinant gene at a specific site in 
vivo. Moreover, this provided one of the first indications that direct gene transfer of 
specific recombinant genes could elicit an immune response to the product of that gene in 
vivo (12). 
These studies suggested that the introduction of the appropriate recombinant genes could 
be used to stimulate the immune system to recognize its product in vivo. In addition, this 
approach provided a general method for the induction of a specific site in vivo. To 
determine whether direct gene transfer might be appropriate for the treatment of disease, a 
murine model of malignancy was developed. Direct gene transfer of an allogeneic 
histocompatibility complex gene into a murine tumor elicits an immune response not only 
to the foreign MHC gene but also to previously unrecognized tumor-associated antigens. 
These immune responses are T cell-dependent, and these tumor-associated proteins are 
recognized within the context of the self major histocompatibility complex. In animals 
presensitized to a specific MHC haplotype, direct gene transfer into established tumors 
could attenuate tumor growth or, in some cases, lead to complete tumor regression (11). 
These studies demonstrate that direct gene transfer of foreign MHC genes into tumors have 
potentially therapeutic effects that may be appropriate for the treatment of malignancy. 
1.2.2 Immunotherapy of Malignancy 
In some instances, the immune system appears to contribute to the surveillance and 
destruction of neoplastic cells, either by mobilization of cellular and humoral immune 
effectors. Cellular mediators of anti-tumor activity include MHC-restricted cytotoxic T 
cells, natural killer (NK) cells (15,16) and lymphokine-activated killer (LAK) cells (17). 
Cytolytic T cells which infiltrate tumors have been isolated and characterized (18). These 
tumor infiltrating lymphocytes (TIL) selectively lyse cells of the tumor from which they 
were derived (3,19). Macrophages can also kill neoplastic cells through antibody-dependent 
mechanisms (20,21), or by activation induced by substances such as BCG (22). 
Cytokines can also participate in the anti-tumor response, either by a direct action on cell 
[ 210 ] 
Recombinant DNA Research, Volume 19 
