Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma.
OBJECTIVE
We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial.


METHODS
Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered 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 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed.


CONCLUSIONS
Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.
Salgia
Ravi
R
Department of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02215, USA.
Lynch
Thomas
T
Skarin
Arthur
A
Lucca
Joan
J
Lynch
Cathleen
C
Jung
Ken
K
Hodi
F Stephen
FS
Jaklitsch
Michael
M
Mentzer
Steve
S
Swanson
Scott
S
Lukanich
Jean
J
Bueno
Raphael
R
Wain
John
J
Mathisen
Douglas
D
Wright
Cameron
C
Fidias
Panos
P
Donahue
Dean
D
Clift
Shirley
S
Hardy
Steve
S
Neuberg
Donna
D
Mulligan
Richard
R
Webb
Iain
I
Sugarbaker
David
D
Mihm
Martin
M
Dranoff
Glenn
G
D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D003131:Combined Modality Therapy; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D008297:Male; D008875:Middle Aged
D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor