Killing 2 birds with 1 stone

Tellam and colleagues (page 4535) have covalently modified an oncogene to increase its efficacy and safety as a DNA cancer vaccine. Cancer immunotherapy offers the potential to eliminate malignant cells with minimal side effects. Finding appropriate target antigens for this approach is critical, since many tumors are heterogeneous or genetically unstable. This is illustrated by the occurrence of MelanA-negative tumors after the infusion of MelanA-specific cytotoxic T cells (CTLs) for the adoptive immunotherapy of melanoma.¹  Targeting oncogenes for cancer immunotherapy should reduce the risk of CTL escape mutants, since oncogenes are indispensable for maintaining the transformed phenotype of malignancies and cannot be mutated or deleted. Incorporating functional oncogenes into DNA cancer vaccines carries the inherent risk of inducing malignancies. This safety concern has been addressed in the past by combining individual epitopes derived from oncogenes.²  However, this strategy requires prior knowledge of epitopes and potentially limits the broadness of the elicited immune response.

Tellam and colleagues used a different strategy to overcome this safety concern without altering the amino acid sequence of an oncogene. In the present study, the authors abrogated the oncogenic potential of latent membrane protein 1 (LMP1), an Epstein-Barr virus (EBV) oncogene, by conjugating it to ubiquitin. The ubiquitin proteolytic pathway plays a central role in many cellular processes, and ubiquitination has been used in the past to enhance the immune response to subdominant antigens.³  The authors found that covalently conjugating LMP1 to ubiquitin not only increased the cellular immune response to LMP1 as judged by a model epitope but also abrogated its transformation potential in vitro and in vivo.

This result may have implications for the future design of cancer vaccines. To determine whether ubiquitination is the best strategy to increase the safety and immunogenicity of tumor antigens requires further evaluation, since the ability of ubiquitin to enhance immunogenicity of antigens is not universal.⁴  In addition, targeting antigens preferentially for major histocompatibility complex (MHC) class I presentation to activate CD8⁺ T-cell responses by ubiquitination might decrease the generation of MHC class II epitopes, which are essential for the activation of CD4⁺ helper T cells. Another strategy to increase the immunogenicity of oncogenes has been their fusion to heat shock proteins.⁵  In light of the results of Tellam and colleagues it seems worthwhile to examine the function of these fusion proteins. Modified oncogenes might increase not only cancer vaccine efficacy but also safety.