Immunogenetic therapy of human melanoma utilizing autologous tumor cells transduced to secrete granulocyte-macrophage colony-stimulating factor.
We performed a clinical study of five patients with melanoma to evaluate the immunobiological effects of retrovirally transduced autologous tumor cells given as a vaccine to prime draining lymph nodes. Patients were inoculated with both wild-type (WT) and GM-CSF gene-transduced tumor cells in different extremities. Approximately 7 days later, vaccine-primed lymph nodes (VPLNs) were removed. There was an increased infiltration of dendritic cells (DCs) in the GM-CSF-secreting vaccine sites compared with the WT vaccine sites. This resulted in a greater number of cells harvested from the GM-CSF-VPLNs compared with the WT-VPLNs at a time when serum levels of GM-CSF were not detectable. Four of five patients proceeded to have the adoptive transfer of GM-CSF-VPLN cells secondarily activated and expanded ex vivo with anti-CD3 MAb and IL-2. One patient had a durable complete remission of metastatic tumor. Utilizing cytokine (IFN-gamma, GM-CSF, IL-10) release assays, GM-CSF-VPLN T cells manifested diverse responses when exposed to tumor antigen in vitro. In two of two patients, GM-CSF-VPLN T cell responses were different from those of matched WT-VPLN cells. This study documents measurable immunobiologic differences of GM-CSF-transduced tumor cells given as a vaccine compared with WT tumor cells. The complete tumor remission in one patient provides a rationale to pursue this approach further.
Chang
A E
AE
Division of Surgical Oncology, University of Michigan, Ann Arbor 48109, USA.
Li
Q
Q
Bishop
D K
DK
Normolle
D P
DP
Redman
B D
BD
Nickoloff
B J
BJ
D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000627:therapeutic use*; D017690:Cell Transplantation; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive; D007376:Interleukin-2 / Q000627:therapeutic use; D008198:Lymph Nodes / Q000166:cytology*; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation
D019496:Cancer Vaccines; D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor