Improvement of cancer vaccination at older age

C. Gravekamp, S.H. Kim, F. Castro
Pacific Medical Center Research Institute, San Francisco, CA

Age is the single most important risk factor for cancer and every strategy for postponing human senescence ultimately relies on developing efficient ways of eradicating neoplastically transformed cells from the body. Although conventional treatments have been improved against primary tumors, they are less effective against metastases. Indeed, most cancer patients do not die from the primary tumor, which can be effectively diagnosed and removed, but as a result of metastasis. The most promising intervention to eliminate metastatic cells is through a vaccine designed on the basis of the highly diverse set of genetic attributes specific for the cancer. While the potential for cancer vaccines have been recognized since Paul Ehrlich proposed his immune surveillance theory in 1909, results thus far have been disappointing. Incomplete detail as to how the immune system responds to cancer and a lack of suitable pre-clinical model systems reflecting the age at which spontaneous tumors usually manifest have thus far prevented the emergence of cancer vaccines of high efficacy. This situation is now changing rapidly.

We have used immune competent mouse models for specific human cancers to develop and test genetic vaccines. We obtained evidence that vaccination with Mage-b, a tumor-associated antigen homologous to human MAGE frequently expressed in human breast tumors, was highly effective against breast cancer metastases at young age but much less so at old age. This age-related reduction in vaccine efficacy appeared to be due to an age-related T cell unresponsiveness. To obtain more insight how to improve cancer vaccination at older age, various immunization strategies and DNA delivery systems were compared in immune competent young and old mice with metastatic breast cancer. Our results suggest that vaccination, based on the activation of innate immune responses, may be most effective. Combination therapies of vaccines with non-toxic compounds that may further improve vaccine efficacy at older age are currently under investigation.