1. BACKGROUND AND PRELIMINARY STUDIES 
1.1 Introduction 
Immunologic surveillance (1) is believed to be one means by which cells undergoing malignant 
transformation are eliminated from the body. Although established cancers escape this potential control 
mechanism, the possibility that autologous cellular immunity could be stimulated to kill cancer cells led 
to a number of therapeutic trials of interleukin (II) -2(1). These studies demonstrated that responses 
could be obtained even in highly resistant neoplasms, such as advanced renal cancer and melanoma. 
Although the response rate was low, and the responses generally partial and short-lived, some lengthy 
complete remissions resulted. The effectiveness of 11-2 was not enhanced by the co-administration of 
ex vivo cultivated LAK (lymphokine activated killer) cells or TIL (tumor infiltrating lymphocytes) (2). 
Investigators are currently exploring the value of markedly reduced doses of 11-2 to diminish the 
substantial toxicity that results from its systemic administration. Developments in gene transfection 
present an alternate approach to modulate the immune response to cancer. It is now feasible to insert 
the genes for the production of interleukins directly into cells. After transfection, these cells can be 
returned to the patient where interleukins can be produced locally to induce an anti-tumor response, as 
has been demonstrated in animal systems at the University of Miami (3) and elsewhere (4,5). The 
intent is that lymphocytes activated locally by a combination of interleukins and tumor surface antigens 
will yield a tumoricidal response not only to the administered transfected interleukin-expressing cancer 
cells but also to the nontransfected cancer cells remaining in the patient. 
1.2 Background 
The benefit from conventional cancer treatment modalities has plateaued, and new directions are 
needed to improve the outcome for patients with cancer. Immunologic modulation of the host in order 
to develop an autologous cytocidal attack on the cancer cells is an increasingly appealing alternative to 
the modalities of chemotherapy and radiation therapy. 
White blood cells that are capable of lysing cancer cells include natural killer (NK) cells, 
lymphokine-activated killer (LAK) cells, cytotoxic T lymphocytes (CTL), and activated macrophages. 
Of these, the cancerocidal activities of LAK cells have been the most extensively studied, largely 
through the work of Rosenberg and colleagues (1). The potent lymphokine, interleukin-2 (11-2), 
produces LAK cells from precursor lymphocytes and stimulates LAK cell proliferation. The LAK cells 
have been characterized phenotypically as non-adherent, non-NK (5) cells that were non-T, non-B and 
HLA class II negative (6). It now appears that 11-2 exposure causes either the generation of CD3- (T 
cell marker), CD16+ (Fc receptor for polymeric IgG) LAK cells by activation of NK cells (CD3- 
,CD16+) (7-11) or CD3 + ,CD16- LAK cells from activated T cells (7,12). The proportion of the 
different types of LAK cells and whether increased NK cell production also occurs after 11-2 stimulation 
depends on the setting (in vivo or in vitro) and dose and duration of exposure to 11-2 (7,13,14). 
Functionally, in vitro, LAK cells lyse NK-sensitive as well as NK-resistant cell lines (15) and cells that 
do not express detectable tumor specific antigens (14). Despite their broad range of lytic capability, 
LAK cells are not non-specific killer cells. In vitro, they lyse autologous tumor cells and fresh 
allogeneic tumor cells, but not normal lymphocytes (15). LAK cells are lytic for both autologous and 
allogeneic acute myeloid and lymphoid leukemia and lymphoma cells (16). Although exposure to 
antibodies against HLA Class I and II antigenic determinants blocks this activity against allogeneic 
targets, autologous cell target kill is unaffected. This lack of H LA-restricted cell killing makes it 
possible for LAK cells to destroy tumor cells that fail to or weakly express histocompatibility antigens 
(17). At the same time, it is well to realize that the subset of LAK cells derived from T lymphocytes 
does require HLA class I antigen expression for maximum effectiveness. 
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