Protocol ID93-008 
Page 1 
OBJECTIVES 
Our long term goal is to develop an effective adoptive immunotherapy strategy for 
epithelial ovarian cancer (EOC) utilizing T-cell lines derived from ovarian tumor 
infiltrating lymphocytes (TIL). To achieve this goal it is important to determine that 
these ovarian TIL lines concentrate at metastatic sites in uiuo. Gene transfer technology 
now offers a reliable and sensitive method to track TIL to tumor sites over a prolonged 
period of time. We therefore plan to determine: 
1.1 The feasibility of detecting CD3+CD8+ Tll^derived T cells that have been marked with 
the gene for Neomycin phosphotransferase encoded in a safety modified retroviral vector 
(GlNa) at tumor sites after IP injection, and 
1.2 The fold of enrichment of CD3+CD8+ marked TIL at tumor sites. 
BACKGROUND AND RATIONALE 
2.1 Ovarian Cancer 
EX)C is responsible for the highest mortality among patients with gynecologic malignancies 
with a 39% overall survival at 5 years (1). Moreover only 20% of patients with EOC 
diagnosed in stages III and IV survive 5 years. Postsurgery combination chemotherapy 
regimens that includes cisplatin or carboplatin produces an overall initial response rate of 
60-80% (2,3). The majority of these patients ultimately progress or relapse due to primary 
or acquired drug resistance (4). There is evidence that salvage therapy with intraperitoneal 
IP approaches such as high dose cisplatin may benefit certain patients with minimal 
residual disease (5). In addition, recent phase II data on the activity of systemically 
administered taxol in platinum refractory ovarian cancer patients looks promising, 
although there are only few complete responses and considerable toxicity with this 
treatment. In consideration of the above modest survival rates achieved, current treatment 
modalities for ovarian cancer leave much to be desired. 
2.2 Cytokine activated killer cells 
Potentiation of an autologous tumor-specific immune response is a central goal of the 
biological therapy of cancer. In a variety of murine models therapy with the cytokine 
interleukin-2 (rIL-2) alone can result in significant tumor regressions (reviewed in 6). 
Potential mechanisms involved in this antitumor effect include the activation of lymphokine 
activated killer (LAK) cells, generation of cytotoxic T-lymphocytes against the tumor, and 
the secondary induction of other cytokines such as tumor necrosis factor a (TNF) or rlFN-y. 
Clinical responses, including durable complete remissions were obseiwed in cancer patients 
treated with ex-vivo activated LAK cells and high doses of rIL-2. Complete plus partial 
response rates in initial clinical trials approximated 20 percent in melanoma, 30 percent in 
renal cell carcinoma, 10 percent in colorectal carcinoma (7,8), and 20 percent in ovarian 
cancer (9,10). However, these responses are comparable to those observed by rIL^2 alone. 
Individual responses have been noted in patients with other malignancies including lung 
carcinoma, Hodgkin’s and non-Hodgkin’s lymphomas, but comparatively few patients have 
been treated with malignancies other than melanomas, renal cell, or colon carcinoma. 
While an advantage of LAK cells is the relative ease with which they may be generated by 
cultivation of peripheral blood lymphocytes obtained by lymphocytophoresis in culture 
medium containing high doses of rIL-2, a significant disadvantage is the fact that these 
cells do not target to sites of malignant disease in radiolabeled trafficking studies, a fact 
that underlines the lack of specificity by LAK cells. This failure to concentrate at tumor 
sites may be partially responsible for the results noted to date in comparative trials of high 
dose rll^2 with or without ex-vivo activated LAK cells in melanoma, which demonstrate 
little or no advantage to the added LAK cells (7). Although LAK cells alone do not appear to 
add substantially to rlL-2 treatment alone (11), the treatment with TIL + rIL-2 have been 
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