DNA vaccination with HuD inhibits growth of a neuroblastoma in mice.
Some patients with small cell lung cancer (SCLC) or neuroblastoma develop an immune response against HuD, a human homologue of the Drosophila protein, elav, which is expressed in the nucleus and to a lesser degree the cytoplasm of neurons and tumor cells. This immune response is characterized by antibodies (anti-Hu) that at high titers are associated with a disease called paraneoplastic encephalomyelitis/sensory neuronopathy, in which infiltrates of T cells are found in the tumor and nervous system. Although all SCLCs express HuD, anti-Hu antibodies are identified in only 17% of patients with SCLC, usually at low titers, and are associated with indolent tumor growth. To determine whether the anti-Hu immune response causes indolent tumor growth, we developed an animal model using HuD DNA immunization. We found that a plasmid coding for a secreted form of HuD induced a strong and specific anti-Hu response. Immunized animals were challenged by s.c. implantation of a neuroblastoma cell line that constitutively expresses HuD. When compared with controls, mice immunized with the secreted HuD showed significant tumor growth inhibition (51% reduction volume; P = 0.0012), and 14% of them had complete tumor rejection. Tumors from these animals showed three times more CD3+ lymphocytic infiltrates than those from control mice and had a higher CD8+:CD4+ ratio. None of the animals developed neurological deficits or neuropathological evidence of nervous system pathology. In this mouse model of neuroblastoma, DNA immunization with HuD resulted in tumor growth inhibition but did not induce neurological disease. This model closely mimics the clinical course of more indolent tumor growth seen in patients with the anti-Hu immune response.
Carpentier
A F
AF
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Rosenfeld
M R
MR
Delattre
J Y
JY
Whalen
R G
RG
Posner
J B
JB
Dalmau
J
J
D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology*; D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007167:Immunotherapy; D016131:Lymphocyte Subsets / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins; D009447:Neuroblastoma / Q000097:blood / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000627:therapeutic use
D000906:Antibodies; D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; C498010:ELAVL4 protein, human; C498011:Elavl4 protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D019444:Vaccines, DNA