1.0 Objectives 
1.1 Evaluate the safety of subcutaneous injections with irradiated autologous or allogeneic HLA-A2 
positive glioblastoma cells genetically modified to express the gene for IL-2. 
1.2 Examine the effects of these injections on tumor growth in vivo. 
1.3 Assess whether the injections induce cellular or humoral anti-tumor immune responses. 
1.4 Compare the anti-tumor effects and immune responses induced by injections with genetically 
modified HLA-A2 positive autologous versus allogeneic tumor cells. 
2.0 Background/Rationale 
2.1 Interleukin-2 Cancer Immunotherapy in Human Subjects 
Recent advances in our understanding of the biology of the immune system have lead to the identification 
of important modulators of immune responses (1-3). These agents mediate many of the immune 
responses involved in anti-tumor immunity. Several of these cytokines have been produced by 
recombinant DNA methodology and evaluated for their anti-tumor effects. In experimental clinical trials, 
the administration of cytokines and related immunomodulators has resulted in objective tumor responses 
in patients with various types of neoplasms (4-7). 
Interleukin-2 (IL-2) is an important cytokine in the generation of anti-tumor immunity (4). In response to 
tumor antigens, a subset of lymphoc>^es termed helper T-cells secrete small quantities of IL-2. This IL-2 
acts locally at the site of tumor antigen stimulation to activate cytotoxic T-cells and natural killer cells 
which mediate systemic tumor cell destruction. Intravenous, intralymphatic or intralesional 
administration of IL-2 has resulted in clinically significant responses in some cancer patients (4-6). 
However, severe toxicities (hypotension and edema) limit the dose and efficacy of intravenous and 
intralymphatic IL-2 administration (5,7). The toxicity of systemically administered cytokines is not 
surprising since these agents mediate local cellular interactions and they are normally secreted in only 
very small quantities. 
To circumvent the toxicity of systemic IL-2 administration, several investigators have examined 
intralesional injection of IL-2. This approach eliminates the toxicity associated with systemic IL-2 
administration (8,9). However, multiple intralesional injections are required to optimize therapeutic 
efficacy (8,9). These injections will be impractical for many patients, particularly when tumor sites are 
not accessible for direct injection without potential significant morbidity. 
The aim of this study is to demonstrate the safety of a novel and more practical method of IL-2 cancer 
immunotherapy. In this approach, a patient's tumor cells are genetically modified to express and secrete 
IL-2. The genetically modified cells are then employed in subcutaneous immunizations to induce 
systemic anti-tumor immunity. 
This approach provides the benefit of local IL-2 administration and obviates the need for multiple 
intralesional injections. The amount of IL-2 secreted by the genetically modified cells is sufficient to 
induce anti-tumor immunity but is too low to produce systemic toxicity. In addition, the continuous 
expression of functional amounts of IL-2 may also produce greater augmentation of anti-tumor immune 
responses compared to that obtained by intermittent cytokine injections. 
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Recombinant DNA Research, Volume 19 
