Methods for improving the immune responses against tumors, especially CTL responses, are likely 
to be therapeutically beneficial to cancer patients. A variety of approaches have been used to 
engender non-specific augmentation of the immune systems of cancer patients. For instance, 
lymphokines such as IL-2, a-IFN, and more recently, y-IFN have proven to be therapeutically 
useful, although efficacy is limited and toxicity associated with systemic administration is 
considerable (8-10). y-IFN and IL-2 presumably function as growth and activation factors (11-15) 
to tumor-reactive immune cells such as CTL, macrophages, natural killer (NK), and lymphokine 
activated killer / tumor infiltrating lymphocytes (LAK/TIL) (16) at the site of the tumor, possibly to 
overcome immune suppression. y-IFN also increases the expression of MHC proteins on the 
surface of tumor cells to improve antigenic presentation (17, 18). The remaining systemicly- 
available lymphokine protein presumably does not contribute to tumor- specific immunity, but does 
lead to significant toxicity. Systemic injection of lymphokines is thus a highly inefficient way to 
deliver these critically important proteins to their site of action, the tumor. 
Another approach which has been used extensively by ourselves and others to activate the immune 
system of cancer patients is active, specific immunotherapy (ASI). In this approach, a patient's 
own tumor is removed and dissociated to a single cell suspension that is inactivated and re-injected, 
with or without additional immunological adjuvants (19-23). It is thought that tumor-specific 
antigens are somehow presented more effectively to the immune system when the tumor is 
presented in this manner. The resultant activation of cytolytic immune cells (such as CTL) have 
had modest but statistically significant response rates (19, 20). 
Another possibility is to activate anti-tumor immunity by combining the tumor specificity of ASI 
with the general immune stimulation induced by lymphokines, such as y-IFN. One approach that 
would assure the continued presence of y-IFN locally around tumor cells is to introduce 
constitutively expressed lymphokine genes into the tumor cells. The resultant constitutive, low 
level production of y-IFN should specifically increase the level of MHC (the antigen presenting 
proteins) on the surface of tumor cells. In addition, y-IFN should be secreted locally around the 
tumor and thus aid the growth and activation of local immune cells (such as CTL, macrophages, 
and NK cells, 16) as they respond specifically to tumor antigen. The concentrated, local presence 
of the immune-activating y-IFN may thus help overcome immune anergy. The total amount of 
lymphokine should then be quite low, but it should be concentrated where it would be most 
effective, namely at the site of tumor cells. The overall effect of lymphokine gene transfer would 
be to "flag" the tumor cell as something that the immune system should carefully scrutinize and 
respond against. The resultant boost in tumor specific immunity could result in improved 
responses compared with non-gene-modified ASI approaches (Fig 1). 
Recombinant DNA Research, Volume 17 
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