Induction of therapeutic T-cell responses to subdominant tumor-associated viral oncogene after immunization with replication-incompetent polyepitope adenovirus vaccine

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 4; pp. 1483 - 1489
• Main Authors: DURAISWAMY, Jaikumar, BHARADWAJ, Mandvi, TELLAM, Judy, CONNOLLY, Geoff, COOPER, Leanne, MOSS, Denis, THOMSON, Scott, YOTNDA, Patricia, KHANNA, Rajiv
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2004
• Subjects: Adenoviridae - genetics; Adenovirus; Amino Acid Sequence; Animals; Antineoplastic agents; Base Sequence; Biological and medical sciences; Cell Line; Epitopes, T-Lymphocyte; Epstein-Barr virus; H-2 Antigens - immunology; Hodgkin Disease - therapy; Humans; Immunization; Medical sciences; Mice; Molecular Sequence Data; Nasopharyngeal Neoplasms - therapy; Pharmacology. Drug treatments; T-Lymphocytes, Cytotoxic - immunology; Tumors; Vaccines, Synthetic - therapeutic use; Viral Matrix Proteins - genetics; Viral Matrix Proteins - immunology; Viral Vaccines - therapeutic use; Virus Replication; Virus; Prevention; Immunization; Adenoviridae; Immune response; Treatment; Replication; Vaccine; Malignant tumor; Onc gene; Gene therapy
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-2196

The EBV-encoded latent membrane proteins (LMP1 and LMP2), which are expressed in various EBV-associated malignancies have been proposed as a potential target for CTL-based therapy. However, the precursor frequency for LMP-specific CTL is generally low, and immunotherapy based on these antigens is often compromised by the poor immunogenicity and potential threat from their oncogenic potential. Here we have developed a replication- incompetent adenoviral vaccine that encodes multiple HLA class I-restricted CTL epitopes from LMP1 and LMP2 as a polyepitope. Immunization with this polyepitope vaccine consistently generated strong LMP-specific CTL responses in HLA A2/K(b) mice, which can be readily detected by both ex vivo and in vivo T-cell assays. Furthermore, a human CTL response to LMP antigens can be rapidly expanded after stimulation with this recombinant polyepitope vector. These expanded T cells displayed strong lysis of autologous target cells sensitized with LMP1 and/or LMP2 CTL epitopes. More importantly, this adenoviral vaccine was also successfully used to reverse the outgrowth of LMP1-expressing tumors in HLA A2/K(b) mice. These studies demonstrate that a replication-incompetent adenovirus polyepitope vaccine is an excellent tool for the induction of a protective CTL response directed toward multiple LMP CTL epitopes restricted through common HLA class I alleles prevalent in different ethnic groups where EBV-associated malignancies are endemic.