INTRODUCTION 
1 . 1 Significance 
Interleukin-2 (IL-2) has become the mainstay for many immunotherapies. It 
has been used alone, as well as in conjunction with a variety of antibodies, 
adoptive transfer of cellular reagents, and other cytokines. Only 25 - 35% 
response rates in selected tumors, notably melanoma and renal cell cancer, have 
been noted. Many attempts to further extrapolate these findings to other tumors 
have been largely unsuccessful. Recently, we've evaluated the role of 
Interleukin-4 (IL-4) when given alone, and subsequently together with IL-2 in a 
group of patients at the National Cancer Institute. A total of 84 treatment 
courses in 73 patients allowed significant information to be attained regarding 
the maximal tolerated dose of the combination, and information regarding efficacy 
of IL-2 and IL-4. No antitumor efficacy was noted with IL-4 alone, although 
significant responses were noted in patients with renal cell carcinoma, melanoma, 
and interestingly, a single patient with breast carcinoma, with the combination 
of IL-2 and IL-4. 
The adoptive transfer of tumor infiltrating lymphocytes, cells which have 
been grown directly from human melanomas in combination of IL-2 and IL-4, has 
been shown to cause successful antitumor response in approximately 40 - 45% of 
patients. Currently, such cells for adoptive immunotherapy protocols are grown 
in combinations of IL-2 and IL-4. It is hoped that administration of TILs in the 
context of IL-2 and IL-4 administration in vivo would enhance the efficacy of 
these therapies. Since IL-2 and IL-4 serve as major T-cell growth factors, and 
likewise cause egress of lymphoid cells into the peripheral tissues, in selected 
patients we will use gene transduced TILs using retroviral vectors. These have 
previously demonstrated at the NCI to be useful in the monitoring of traffic of 
such cells over long periods of time and in assessing some of the immunologic 
parameters in such patients. These will be helpful in optimizing this treatment. 
1 . 2 Background/Preliminarv Stuuj.es 
There are now three described T-cell growth factors (TCGF) which mediate 
expansion of human T-cells, expecially following specific T-cell activation. 
These include Interleukin-2 (1,2), Interleukin-4 (3,4), and Interleukin- 7 (5-7). 
We have utilized IL-2 alone or in conjunction with other cytokines, monoclonal 
antibodies, or the adoptive t-ransfer of activated cells in over 652 cancer 
patients and demonstrated significant anti -tumor effects with objective 
regression of cancer in--2.0 - 35% of patients with selected advanced metastatic 
cancers (8). The result.s of immunotherapy with IL-2 alone is shown in Table 1. 
The toxic side effects of these IL-2 based treatments included malaise, nausea 
and vomiting, hypertension, fluid retention and organ dysfunction. A search for 
other agents capable of acting directly on human lymphoid cells has been carried 
out in our laboratory for a number of years . 
Interleukin-4 (IL-4) was previously defined as a B-cell stimulating factor 
(BSF-1) and has also been referred to as B-cell differentiation factor, mast 
cell growth factor II and T-cell growth factor II (9). In murine studies, IL-4 
was shown to enhance the generation of lymphokine activated killer cell (LAK) 
activity (10) , enhance the generation of the enzyme surrogate associated with 
cytotoxicity, BLT esterase (11) and to serve as a major T-cell growth factor 
(12) . Human recombinant IL-4 has been purified from the product of a recombinant 
cDNA clone isolated by cross hybridization with a murine IL-4 cDNA clone. It is 
currently available for clinical trials following production in a yeast 
expression system. It is a mutein with two amino acids substituted to preclude 
glycosylation and has a nonglycosylated molecular weight of approximately 15,000 
dal tons . 
[836] 
Recombinant DNA Research, Volume 14 
