Activation of human T cells by a tumor vaccine infected with recombinant Newcastle disease virus producing IL-2.
A new recombinant (rec) Newcastle disease virus (NDV) with incorporated human interleukin 2 (IL-2) as foreign therapeutic gene [rec(IL-2)] will be described. The foreign gene in rec(IL-2) did not affect the main features of NDV replication nor its tumor selectivity. Biologically active IL-2 was produced in high amounts by tumor cells infected with rec(IL-2). Tumor vaccine cells infected by rec(IL-2) stimulated human T cells to exert anti-tumor activity in vitro in a tumor neutralization assay. These effects were significantly increased when compared to vaccine infected by rec(-) virus without IL-2 gene. After incubation with rec(IL-2) infected tumor cells, T cells showed increased expression of the activation marker CD69 and produced increased amounts of IFNgamma when compared to T cells co-incubated with rec(-) infected tumor cells. CD8 T cells incubated with rec(IL-2) infected tumor cells showed upregulation of perforin, cell surface exposure of the degranulation marker CD107a and increased anti-tumor cytotoxic activity. Purified T cells from lymph nodes of head and neck squamous cell carcinoma (HNSCC) patients could be stimulated to secrete IFNgamma in an ELISPOT assay upon 40 h of stimulation with rec(IL-2) infected autologous tumor cells [ATV-rec(IL-2)] but not upon stimulation with rec(IL-2) infected allogeneic U937 tumor cells. This suggests direct activation of patient derived tumor antigen-specific memory T cells by ATV-rec(IL-2). In conclusion, the already inherent immunostimulatory properties of NDV could be further augmented by the introduction of the therapeutic gene IL-2. Active specific immunization of patients with ATV-rec(IL-2) should provide the microenvironment at the vaccination site with IL-2 and avoid side effects as seen after systemic IL-2 application.
Janke
Markus
M
Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Peeters
Ben
B
Zhao
Heng
H
de Leeuw
Olav
O
Moorman
Rob
R
Arnold
Annette
A
Ziouta
Yvonne
Y
Fournier
Philippe
P
Schirrmacher
Volker
V
D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D019496:Cancer Vaccines / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000821:virology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000821:virology; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation; D009522:Newcastle disease virus / Q000235:genetics*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D020298:U937 Cells; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019496:Cancer Vaccines; D007376:Interleukin-2; D037181:Lectins, C-Type; D000099192:CD69 Antigens