Optimizing cancer immunotherapy trials: Back to basics

Abstract

Attempts to raise effective immunity against cancer are benefiting from information on the nature of the immunity involved and its regulation and, perhaps, now it is time to step back and define our approach in molecular terms prior to clinical testing. Although there are immunological differences between mice and patients, results from murine studies are encouraging early 'translation' of concepts to the clinic and it is vital to take immunological principles emerging from mice into clinical vaccine design. One is the requirement to break tolerance against over-expressed self-antigens, a potentially risky procedure but necessary for several cancer targets. A study in this issue of the European Journal of Immunology attempts to do this by using xenogeneic antigens, albeit with variable outcome. The unstated goal is to activate T-cell help but this can be achieved more effectively by harnessing a predictable anti-microbial repertoire. The second issue lies in the delivery of antigen. One strategy is "prime/boost" using DNA priming and boosting with a viral vector; however, this induces blocking immunity against viral proteins, and must be used judiciously. There are other physical methods to increase immunity such as electroporation, which can itself be used in 'prime/boost' sequence. These twin problems of engagement of T-cell help and delivery of adequate antigen can now be addressed by applying immunological logic to cancer vaccines.See accompanying article http://dx

Hepatitis B virus core antigen epitopes presented by HLA‐A2 single‐chain trimers induce functional epitope‐specific CD8+ T‐cell responses in HLA‐A2·1/Kb transgenic mice

“…Kidney and liver damage caused by circulating immune complexes as a result of the long‐term persistence of antigen and antibody was reported after DNA vaccination in an animal model 24 . In the context of HBV infection, surface antigen and core antibodies are usually present during acute and chronic HBV infection; a vaccination strategy for clinical application should consider the existing over‐expressed antigen and persistent antibodies 25 . More importantly, HBV recurrence following dominant epitope mutation after medical treatment often occurs, and low‐affinity (non‐dominant) epitopes that are less likely to be subject to immune selection and mutation may play even more vital roles in therapeutic vaccination 26 .…”

DNA Vaccines: Developing New Strategies against Cancer

“…Additional strategies to activate effective immunity against poorly immunogenic tumor antigens employ the "DNA fusion genes vaccines" to activate T cell help for antitumor responses. The CD4 + Th cell, as pivotal cell of the immune response able to induce high levels of immunity and the maintenance of the response, has been extensively studied by Stevenson and coworkers [97]. The requirement for foreign sequences to induce Th for the B-cell response and to help the CTL response has been known for many years [98,99].…”