Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.
OBJECTIVE
Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer.


METHODS
Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 x 10(6), 4 x 10(6), or 1 x 10(7) tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals.


RESULTS
Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106 cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.


CONCLUSIONS
Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.
Soiffer
Robert
R
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Hodi
F Stephen
FS
Haluska
Frank
F
Jung
Ken
K
Gillessen
Silke
S
Singer
Samuel
S
Tanabe
Kenneth
K
Duda
Rosemary
R
Mentzer
Steven
S
Jaklitsch
Michael
M
Bueno
Raphael
R
Clift
Shirley
S
Hardy
Steve
S
Neuberg
Donna
D
Mulligan
Richard
R
Webb
Iain
I
Mihm
Martin
M
Dranoff
Glenn
G
D000256:Adenoviridae; D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D003131:Combined Modality Therapy; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005818:Genetic Engineering; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006968:Hypersensitivity, Delayed; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor