A case report: immune responses and clinical course of the first human use of granulocyte/macrophage-colony-stimulating-factor-transduced autologous melanoma cells for immunotherapy.
The first use of granulocyte/macrophage-colony-stimulating-factor-transduced, lethally irradiated, autologous melanoma cells as a therapeutic vaccine in a patient, with rapidly progressive, widely disseminated malignant melanoma resulted in the generation of a novel antitumour immune response associated with partial, albeit temporary, clinical benefit. An initially negative reaction to non-transduced, autologous melanoma cells was converted to a delayed-type hypersensitivity (DTH) reaction of increasing magnitude following successive vaccinations. While intradermal vaccine sites showed prominent dendritic cell accrual, DTH sites revealed a striking influx of eosinophils in addition to activated/memory T lymphocytes and macrophages, recalling the histology of challenge tumour cell rejection in immune mice. Cytotoxic T lymphocytes (CTL) reactive with autologous melanoma cells were detectable at high frequency after vaccination, not only in limiting-dilution analysis, but also in bulk culture without added cytokines. Clonal analysis of CTL showed a conversion from a purely CD8+ response to a high proportion of CD4+ clones following vaccination. A prominent acute-phase response manifested by a five- to tenfold increase in C-reactive protein was observed, as was a systemic eosinophila. Vaccination resulted in the regression of axillary lymphatic metastases, stabilisation of pulmonary metastases, and a dramatic, reversible increase in cerebral oedema associated with multiple central nervous system metastases: however, lesions in the adrenal glands, pancreas and spleen proved refractory. The antitumour effects and immune response were not detectable 2 months following the last vaccination. Irradiation of the extensive cerebral metastases resulted in rapid deterioration and death of the patient.
Ellem
K A
KA
Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, Bancroft Centre, Brisbane, Australia.
O'Rourke
M G
MG
Johnson
G R
GR
Parry
G
G
Misko
I S
IS
Schmidt
C W
CW
Parsons
P G
PG
Burrows
S R
SR
Cross
S
S
Fell
A
A
Li
C L
CL
Bell
J R
JR
Dubois
P J
PJ
Moss
D J
DJ
Good
M F
MF
Kelso
A
A
Cohen
L K
LK
Dranoff
G
G
Mulligan
R C
RC
D001344:Autopsy; D015415:Biomarkers; D001932:Brain Neoplasms / Q000556:secondary; D002097:C-Reactive Protein / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004802:Eosinophilia / Q000209:etiology; D018014:Gene Transfer Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D006968:Hypersensitivity, Delayed; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014182:Transplantation, Autologous; D014611:Vaccination
D015415:Biomarkers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002097:C-Reactive Protein