Harnessing the antigenic fingerprint of each individual cancer for immunotherapy of human cancer: genomics shows a new way and its challenges

Abstract

The idea that individual tumors are antigenically unique has been around since the very dawn of our recognition of adaptive immune response to tumors. That idea has inspired a small number of attempts at individualized immunotherapy of human cancers. Such previous attempts for solid tumors have been hobbled by an inability to define the individually unique antigenic repertoire of tumors because of technological difficulties. The new availability of rapid and cheap high throughput DNA sequencing promises to overcome that hurdle. Using this new ability, coupled with bio-informatic tools, it is now possible to define the immunogenic repertoire of any tumor to a high degree of granularity within a practical time frame and an acceptable cost. The development of these ideas, and a small number of such studies that underscore this promise, is discussed. This new way--of characterizing the tumor immunome through characterization of the tumor genome--has distinct challenges, including selection of the appropriate peptides, choosing methods of immunizations that can incorporate tens of epitopes, and addressing issues of antigenic heterogeneity of tumors. However, tools for meeting these challenges exist and are emergent.

Fig. 1

Antigenic heterogeneity in tumor masses. A schematic showing the emergence of random passenger mutations (that are not required for the transformed phenotype and that do not confer any survival advantage or disadvantage and assuming zero tumor cell death) in a growing tumor mass. The mutation that occurs at the first division of the transformed cell is imprinted on 50 % of the population, while mutations occurring in subsequent cell cycles (red, green, purple, turquoise, and orange, in that order) are presented on increasingly narrower population segments, leading to a tumor with various sub-population of cells expressing different sets of mutations. The figure may appear to suggest (incorrectly) that tumors are actually compartmentalized in this manner: Since newer mutations are as likely to occur in cells that harbor older mutations as in the cells that do not, the tumor mass will actually be a chimera of cells presenting large numbers of overlapping sets of neo-epitopes