T cell responses in melanoma patients after vaccination with tumor-mRNA transfected dendritic cells.
We have developed an individualized melanoma vaccine based on autologous dendritic cells (DCs) transfected with autologous tumor-mRNA. The vaccine targets the unique spectrum of tumor antigens in each patient and may recruit multiple T cell clones. In a recent phase I/II trial, we demonstrated T cell responses against vaccine antigens in 9/19 patients evaluable by T cell assays. Here, we report a follow-up study that was conducted to characterize interesting T cell responses and to investigate the effects of long-term booster vaccination. Two patients were selected for continued vaccine therapy. The clinical follow-up suggested a favorable clinical development in both patients. The immunological data (T cell proliferation/IFNgamma ELISPOT/Bioplex cytokine assays) indicated sustained T cell responses and suggested an enhancing effect of booster vaccinations. Both CD4(+) and CD8(+) T cell responses were demonstrated. From post-vaccination samples, we generated 39 T cell clones that responded specifically to stimulation by mRNA-transfected DCs and 12 clones that responded to mock-transfected DCs. These data clearly indicate a two-component vaccine response, against transfected and non-transfected antigens. T cell receptor (TCR) clonotype mapping, performed on 11 tDC-specific clones, demonstrated that 10/11 clones had different TCRs. The results thus indicate a broad spectrum T cell response against antigens encoded by the transfected tumor-mRNA. We generally observed mixed Th1/Th2 cytokine profiles, even in T cell clones that were confirmed to be derived from a single cell. This finding suggests that cytokine patterns after cancer vaccination may be more complex than indicated by the classic Th1/Th2 dichotomy.
Kyte
Jon Amund
JA
Section for Immunotherapy, Department of Immunology, Cancer Research Institute, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway. j.a.kyte@medisin.uio.no
Kvalheim
Gunnar
G
Lislerud
Kari
K
thor Straten
Per
P
Dueland
Svein
S
Aamdal
Steinar
S
Gaudernack
Gustav
G
D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D012334:RNA, Neoplasm / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D019496:Cancer Vaccines; D016207:Cytokines; D012334:RNA, Neoplasm; D011948:Receptors, Antigen, T-Cell