Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin.
In murine models, transgenic chemokine-cytokine tumor vaccines overcome many of the limitations of single-agent immunotherapy by producing the sequence of T-cell attraction followed by proliferation of tumor antigen-activated clones. The safety and immunologic effects of this approach in humans were tested in 7 patients with relapsed or refractory neuroblastoma. They each received up to 8 subcutaneous injections of a vaccine combining lymphotactin--and interleukin-2 (IL-2)--secreting autologous neuroblastoma cells in a dose-escalating scheme. Adverse events were limited to grade 1 or 2 localized reactions in all patients, pain in 3 patients, and fever in 3 patients. Injection site biopsies revealed increased cellularity caused by infiltration of CD4 and CD8 lymphocytes, eosinophils, and dendritic cells with a decrease in dendritic cells from the first to the second vaccination. Systemically, vaccine was associated with increased tumor recognition as measured by enzyme-linked immunosorbent spot assays. Two patients had interferon-gamma predominant responses and 3 had IL-5 predominant responses. Only 1 patient received all 8 injections, 1 patient stopped the study early, and all other patients progressed before completion of the study. Hence, autologous tumor cell vaccines combining transgenic lymphotactin with IL-2 seem to have little toxicity in humans and can induce an antitumor immune response. In this setting, the immune response was insufficient to overcome active recurrent neuroblastoma.
Russell
Heidi V
HV
Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030 , USA. hvrussel@txccc.org
Strother
Douglas
D
Mei
Zhuyong
Z
Rill
Donna
D
Popek
Edwina
E
Biagi
Ettore
E
Yvon
Eric
E
Brenner
Malcolm
M
Rousseau
Raphael
R
D000293:Adolescent; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D008222:Lymphokines / Q000235:genetics / Q000276:immunology*; D008297:Male; D009447:Neuroblastoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D010524:Peripheral Nervous System Neoplasms / Q000628:therapy*; D012795:Sialoglycoproteins / Q000235:genetics / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination
D019496:Cancer Vaccines; D007376:Interleukin-2; D008222:Lymphokines; D012795:Sialoglycoproteins; C018997:lymphotactin