A phase-I trial using a universal GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) in the formulation of autologous tumor cell-based vaccines for cancer patients with stage IV disease.
BACKGROUND
Significant antitumor T-cell responses are generated in vitro when human lymphocytes are stimulated with autologous tumor cells in the presence of bystander cells transfected with CD40L and GM-CSF. Our goal was to test this bystander-based vaccine strategy in vivo in cancer patients with stage IV disease.


METHODS
Patients received three intradermal vaccine injections (irradiated autologous tumor cells plus GM.CD40L bystander cells) at 28-day intervals. Patients with no disease progression received three additional vaccines at 4, 12, and 24 months. Patients were monitored for toxicity, tumor response, and tumor-specific immune responses.


RESULTS
Twenty-one patients received at least three vaccine injections, with no toxicity attributable to the vaccine. Immunohistochemistry of vaccine injection site biopsies with CD1a and CD86 antibodies confirmed recruitment and activation of dendritic cells. There was no tumor regression after vaccination, but many patients had stable disease, including six of ten melanoma patients. Four patients developed tumor-specific T-cell responses on ELISPOT testing. One patient, who had stable disease for 24 months, demonstrated an increase in MART-1-specific T-cells by tetramer analysis after re-immunization; biopsy of the tumor that progressed 2 years after the onset of vaccination revealed a massive peritumoral and intratumoral T-cell infiltrate.


CONCLUSIONS
Vaccination of cancer patients with autologous tumor cells and GM.CD40L bystander cells (engineered to express GM-CSF and CD40L) is safe, can recruit and activate dendritic cells, and can elicit tumor-specific T-cell responses. Phase-II trials are underway to evaluate the impact of bystander-based vaccines on melanoma and mantle cell lymphoma.
Dessureault
Sophie
S
Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, at the University of South Florida, Tampa, FL 33612, USA. dessursm@moffitt.usf.edu
Noyes
David
D
Lee
David
D
Dunn
Mary
M
Janssen
William
W
Cantor
Alan
A
Sotomayor
Eduardo
E
Messina
Jane
J
Antonia
Scott J
SJ
D000276:Adjuvants, Immunologic / Q000502:physiology / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D024201:Bystander Effect / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology / Q000627:therapeutic use*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy; D004915:Leukemia, Erythroblastic, Acute; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D023201:CD40 Ligand; D016178:Granulocyte-Macrophage Colony-Stimulating Factor