SCIENTIFIC ABSTRACT 
Phase I Study of Non-Replicating Autologous Tumor Cell Therapy Using Cell 
Preparations with and without GM-CSF Gene Transduction in Patients with 
Metastatic Renal Cell Carcinoma 
This phase I study in patients with advanced kidney cancer is undertaken 
with a view toward developing an effective means of treating disseminated 
cancers. The rationale for this trial is based on extensive pre-clinical studies 
in murine tumor models supplemented by in vitro explorations of the genetic 
modification of human renal cell cancer (RCC) cells and vaccine preparation. 
Murine cancer cell lines genetically modified by the MFG retroviral vector 
containing cytokine genes have been screened for therapeutic anti-tumor activity. 
Screening included models of melanoma, sarcoma, renal cancer, lung cancer and 
colon cancer. Of 10 immunostimulatory molecules tested, only GM-CSF consistently 
showed superior antitumor efficacy in every cancer line tested. In both murine 
melanoma (B16) and murine RCC (RENCA), GM-CSF gene transduction enhanced the 
eradication of previously implanted tumors. Lethally irradiated, GM-CSF gene 
transduced murine cancer cells lost none of their potency. The genetically 
manipulated cells did not grow or cause significant toxicities at the site of 
administration . 
With the MFG retroviral vector used in newly optimized in vitro culture 
conditions, over 30% of human RCC cells are transducible with a single 
transduction. In pilot studies, 20 of 22 consecutive primary cultures of RCC 
cells were transduced successfully. No drug selection was required. In these 
feasibility studies MFG retroviral transduction with the human GM-CSF gene 
increased baseline GM-CSF secretion by 10 to 20 fold over non-transduced RCC 
cells. Irradiation experiments defined a dose where patient derived RCC cells 
were rendered non-replicat ive . Fortunately, post-transduction GM-CSF secretion 
was not diminished by irradiation. 
The overall objective of this phase I trial is to evaluate escalating doses 
of irradiated renal carcinoma cells with and without human GM-CSF gene 
transduction for safety of clinical administration and induction of antitumor 
immune responses. In order to distinguish toxicities related to cell dose from 
potential toxicities due to expression of GM-CSF, two clinical dose escalation 
studies are contained in one trial. In one set of patients, escalating doses of 
irradiated, autologous renal cell carcinoma cells (RCC) expanded in short-term 
culture and transduced with the human GM-CSF gene will be tested to determine the 
highest safely tolerated dose. Equivalent cell doses of similarly expanded, 
irradiated, non-transduced tumor cells will be tested in another set of RCC 
patients. Three specific primary study objectives are: 
1. To evaluate the safety and tolerability of skin injections of cultured, 
irradiated, autologous RCC cells as well as similarly prepared RCC cells 
transduced with the human GM-CSF gene secreting the cytokine at 24-48 
ng/10 6 RCC cells/24 hr. The dose range of irradiated RCC cells under 
evaluation is 4X10 6 to 1X10 9 . 
2. To describe and quantitate acute clinical toxicities and long-term 
clinical toxicities of untransduced and GM-CSF gene transduced cell 
injections . 
3. To assay both in vitro and in vivo the contribution of RCC cell GM-CSF 
gene transduction to the induction of specific antitumor immune responses 
relative to irradiated non-transduced RCC cells at equivalent cell doses. 
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Recombinant DNA Research, Volume 17 
