Tumor immunogenicity and responsiveness to cancer vaccine therapy: the state of the art

Abstract

Despite enormous effort, promising pre-clinical data in animal studies and over 900 clinical trials in the United States, no cancer vaccine has ever been approved for clinical use. Over the past decade a great deal of progress has been in both laboratory and clinical studies defining the interactions between developing tumors and the immune system. The results of these studies provide a rationale that may help explain the failure of recent therapeutic cancer vaccines in terms of vaccine principles, in selecting which tumors are the most appropriate to target and instruct the design and implementation of state-of-the-art cancer vaccines.

Figure 1. Differential interactions between immunogenic versus non-immunogenic tumors and the immune system

Tumors develop within tissues and release tumor antigens into local lymphoid organs. For immunogenic tumors (such as melanoma), those antigens lead to cytotoxic T lymphocyte (CTL) activation and subsequent infiltration of the tumor by tumor-antigen specific CTL. The observation that many immunogenic tumors develop in spite of such a response is evidence that immunogenic tumors develop regulatory characteristics that lead to resistance to tumor cell killing by CTL. Non-immunogenic tumors on the other hand (such as NSCLC) release antigens that do not efficiently prime an anti-tumor immune response, and as a result such tumors need not develop regulatory mechanisms to counteract the killing activity of tumor-antigen primed CTL. Therapeutic vaccination aims to prime the immune system against tumor antigens, so it is anticipated that such a response will be more effective against tumors (non-immunogenic) that have not already acquired an immune regulatory phenotype.

Figure 2. Proposed flow-chart for the application of therapeutic cancer vaccines