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 growth or by activating cellular immunity. The cytostatic effects of tumor necrosis 
factor-a (TNF-a) (23) and lymphotoxin (24) can result in neoplastic cell death. 
Interferon-y (IFN-y) markedly increases class I MHC cell surface expression (25,26) and 
synergizes with TNF-a in producing this effect (27). Colony stimulating factors such as 
G-CSF and GM-CSF activate neutrophils and macrophages to lyse tumor cells directly 
(28), and interleukin-2 (IL-2) activates Leu-19+ NK cells to generate lymphokine 
activated killer cells (LAK) capable of lysing autologous, syngeneic or allogeneic tumor 
cells but not normal cells (17,29,30). The LAK cells lyse tumor cells without 
preimmunization or MHC restriction (31). Interleukin-4 (IL-4) also generates LAK cells 
and acts synergistically with IL-2 in the generation of tumor specific killer cells (32). 
Since most malignancies arise in immunocompetent hosts, it is likely that tumor cells 
have evolved mechanism to escape host defenses, perhaps through evolution of 
successively less immunogenic clones (33). Deficient expression of class I MHC 
molecules limits the ability of tumor cells to present antigens to cytotoxic T cells. 
Freshly isolated cells from naturally occurring tumors frequently lack class I MHC 
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