Mutated Ras-transfected, EBV-transformed lymphoblastoid cell lines as a model tumor vaccine for boosting T-cell responses against pancreatic cancer: a pilot trial.

Abstract

Genetically modified lymphoblastoid cell lines (LCL) have been shown to be an attractive alternative source of antigen-presenting cells for cancer vaccination in vitro. We tested their application in patients with pancreatic cancer in a phase I clinical trial. As a model tumor antigen, we selected the point-mutated (codon 12) Ki-Ras p21 oncogene (muRas) frequently (∼85%) present in pancreatic adenocarcinoma. Autologous LCLs were established in vitro by spontaneous outgrowth from peripheral blood lymphocytes of seven pancreatic carcinoma patients and were genetically modified with an episomal Epstein-Barr virus (EBV)-based expression vector to express muRas (muRas-LCL). Weekly vaccinations with subcutaneous injection of 5×10(6) muRas-LCL were done. In six of seven patients, therapeutic vaccination elicited a T-cell response with an increase in the frequency of muRas-specific precursor cytotoxic T lymphocytes in the peripheral blood and positive delayed-type hypersensitivity reactions at the injection site. Besides local reactions and flu-like symptoms, there were no signs of toxicity and no acute EBV infection, onset of EBV-associated lymphoma, or other severe complications. A clinical response (stable disease) was observed for a short time period (2-4 months) in four of seven patients (57%), mostly in earlier tumor stages. Our results indicate that LCL presenting genetically modified antigen represent a valuable and easily available tool for in vivo autologous tumor vaccination. LCL can be transfected with any known tumor antigen and therefore should be further clinically investigated.

• Authors: Boris Kubuschok, Michael Pfreundschuh, Rainer Breit, Frank Hartmann, Martina Sester, Barbara Gärtner, Jochem König, Niels Murawski, Gerhard Held, Carsten Zwick, Frank Neumann
• Journal: Human gene therapy (Hum Gene Ther) Vol. 23 Issue 12 Pg. 1224-36 (Dec 2012) ISSN: 1557-7422 [Electronic] United States
• PMID: 22966960 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• Cytokines

Topics

• Adenocarcinoma (immunology, mortality, therapy)
• Aged
• CD4-Positive T-Lymphocytes (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (administration & dosage, genetics, immunology)
• Cell Line, Transformed
• Chemotherapy, Adjuvant
• Cytokines (immunology, metabolism)
• Female
• Genes, ras
• Herpesvirus 4, Human (genetics, immunology)
• Humans
• Injections, Subcutaneous
• Male
• Middle Aged
• Pancreatic Neoplasms (immunology, mortality, therapy)
• Pancreaticoduodenectomy
• Pilot Projects
• T-Lymphocytes (immunology)
• Transfection
• Treatment Outcome