ABSTRACT
PERSPECTIVES IN CANCER VACCINES The idea that suffering from an infectious disease affords protection against it in the future originated before the birth of modern medicine. The fi rst documentation, dated 429 BC, observed that the survivors of the plague of Athens could not catch the disease a second time. Nonetheless, it is only in the 19th century AD that the fi rst scientifi c proof of principle of vaccination was reported. In 1800, E.A. Jenner published his book “An Inquiry into the Causes and Effects of the Variolae Vaccinae,” where he described his experiments conducted on 23 subjects that were protected from smallpox virus after inoculation with material from cowpox-infected animals. Since then, vaccinology has realized dramatic successes: vaccination is the most relevant public health measure of the past century. Despite striking advances, the idea that not only microbes but also tumor cells could be the target of vaccination strategies is more recent, and initiated with R. Virchow’s studies in 1863, who described the presence of abundant immune cells in the stroma of different tumor lesions. Now it has been universally accepted that the immune system plays a critical role in cancer progression ( 1 ). The incidence of hepatocellular carcinoma has been signifi cantly decreased thanks to the introduction of the hepatitis-B vaccine, while human papillomavirus (HPV) vaccines signifi - cantly prevent HPV-associated cervical malignancies by protecting against HPV infection. However, human cancers with a clear infective etiology account for less than 20% of all tumor cases worldwide. Therefore, cancer vaccinology has been exploiting tumor targets different from cancer-inducing microbes, that is, tumor antigens. Intriguing tumor antigens as vaccine targets were fi rstly identifi ed in melanoma, belonging to the class of tumor-specifi c antigens and cancer testis antigens (CTAs). Many clinical trials showed that cancer vaccines frequently induced the generation of cytotoxic T lymphocytes (CTLs), or more generally elicited immune responses activation, but they inexorably fail to afford a clinically signifi cant advantage in phase III clinical trials. The reason for this unsuccessful outcome is to be found in the suboptimal trial design. Most of the cancer vaccine trials carried out so far have been on endstage patients. This is a limitation to unravel the potential of cancer vaccines, because advanced-stage patients have undergone previous treatments that are potentially harmful for the immune system’s response to vaccination, and a chronic exposure to tumor antigens can lead to dysfunctional T-cell responses. In contrast, vaccination at early tumor stages affords excellent responses and signifi cantly improves survival in preclinical studies. These observations point out the urgent need of evaluating cancer vaccine strategies in early-stage patients to fully exploit their potential.
