The development of gene therapy for the treatment of cancer.
OBJECTIVE
The authors sought to develop new treatments for patients with cancer based on the genetic modification of immune lymphocytes and tumor cells designed to increase the host immune reaction against growing cancers.


METHODS
Retroviral-mediated gene transduction was used to introduce genes into tumor-infiltrating lymphocytes (TIL), and these genetically altered TIL were administered to patients with cancer. Genes coding for cytokines were introduced into tumor cells, and these cells were used to immunize patients against their autologous cancers.


RESULTS
In initial studies, the gene for neomycin phosphotransferase was introduced into the TIL of ten patients with advanced cancer to study the survival and distribution of TIL in humans. These studies showed that retroviral gene transduction is a safe and practical method for adding genes to human cells and led to clinical trials in which the gene for tumor necrosis factor (TNF) was inserted into TIL in an effort to increase their therapeutic effectiveness. Phase I trials are currently underway using TIL that secrete up to 100 times the normal level of TNF. More recently, animal experiments have revealed that transduction of tumor cells with cytokine genes can enhance tumor immunogenicity and, thus, increase the recognition of the tumor as foreign by the host. Clinical trials based on these observations have begun in which patients are immunized against their own autologous tumors that were transduced with the genes for TNF or interleukin-2.


CONCLUSIONS
Attempts at gene therapy for cancer are underway and have opened new possibilities for the development of cancer treatments.
Rosenberg
S A
SA
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Anderson
W F
WF
Blaese
M
M
Hwu
P
P
Yannelli
J R
JR
Yang
J C
JC
Topalian
S L
SL
Schwartzentruber
D J
DJ
Weber
J S
JS
Ettinghausen
S E
SE
D000328:Adult; D002985:Clinical Protocols; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007376:Interleukin-2 / Q000235:genetics; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008545:Melanoma / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D009355:Neomycin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D009355:Neomycin