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

J Duraiswamy, M Bharadwaj, J Tellam, G Connolly… - Cancer Research, 2004 - AACR
J Duraiswamy, M Bharadwaj, J Tellam, G Connolly, L Cooper, D Moss, S Thomson…
Cancer Research, 2004AACR
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 …
Abstract
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/Kb 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/Kb 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.
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