Current Cancer Drug Targets, 2011, 11, 103-110 103 1568-0096/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd. Chronic Vaccination with a Therapeutic EGF-Based Cancer Vaccine: A Review of Patients Receiving Long Lasting Treatment G. Gonzalez*, T. Crombet and A. Lage Center of Molecular Immunology, Calle 216 esq 15 Siboney, Playa, C. Habana, Cuba Abstract: Therapeutic vaccines continue to be one of the most active fields in cancer research. However, despite clear evidence of antitumor effect in laboratory animals, and despite the ability of current vaccine candidates to elicit tumor specific antibodies and T-cells in humans, objective responses in the clinical trials are rare. The role of therapeutic vac- cines in advanced cancer patients, if any, would be to decrease the rate of disease progression and to increase survival and quality of life. Due to the redundant regulatory loops contracting the immune response to antigens that cannot be elimi- nated, such a role would require chronic vaccination, which is at first sight at odds with the classic experience of vacci- nology. During the last decade our team has been developing a therapeutic vaccine for advanced lung cancer, which con- sists of human recombinant Epidermal Growth Factor (EGF) chemically conjugated to a carrier protein from Neisseria meningitides. Several clinical trials have been carried out, showing increase in anti-EGF antibody titers, decrease in plasma EGF concentration and survival advantage in vaccinated patients. In the present paper we review data from 58 pa- tients who were vaccinated monthly for more than one or two years. Long term vaccination was feasible and safe, and there was no evidence of cumulative toxicity. Patients kept high anti-EGF antibody titers during all the time of vaccina- tion, without evidence of immune response exhaustion. Continued vaccination increased the probability to get a high anti- body response, which has been previously shown to be, in turn, associated with a better survival. Observations done in this series of patients suggest that long term therapeutic vaccination is a feasible strategy, worth to be further explored with the aim of transforming advanced cancer into a chronic disease. Keywords: Cancer vaccines, EGF, EGFR, chronic vaccination. INTRODUCTION The possible therapeutic effect of specific active immu- notherapy (therapeutic vaccines) in cancer patients is cur- rently one of the most active fields of cancer immunology [1-3]. More than 60 cancer vaccines in clinical trials are re- ported in the last PhRMa survey of Biotechnology Medicines [4]. However, this scientific field is currently trapped in a rare, apparently contradictory situation. On one hand, com- pelling evidence continues to accumulate which demon- strates that tumours do contain antigens recognizable by the immune system and that immunotherapy can eradicate tu- mours in certain experimental conditions [5-7]. But on the other hand, most large clinical trials of thera- peutic cancer vaccines completed up to now have failed [8, 9], and more than 50 years after the seminal discovery of Tumour Specific Rejection Antigens [10, 11] there is only one vaccine already approved for being used in the clinical practice [12]. Moreover, results of some recent clinical trials have sug- gested that vaccination could also have a detrimental effect [13, 14]. The roots of this contradictory situation are to be found in fundamental immunology. Theories and mechanistic evi- dence about how the immune system works have been based mainly on experiments with acute exposure to non-self *Address correspondence to this author at the Center of Molecular Immu- nology, Calle 216 esq 15 Siboney, Playa, C. Habana, Cuba; Tel: 53 7 2717645; Fax: 53 7 273 3509 & 53 7 272 0644; E-mail: gisela@cim.sld.cu antigens carried by infectious pathogens, which either are rapidly cleared by the immune reaction or rapidly kill the host. The interaction of tumours with the immune system is just the opposite: the targets recognized by antibodies and T- cells are mainly self, or self-like molecules, slowly and chronically interacting with the system, and which generally cannot be eliminated. Then, although with therapeutic cancer vaccines, as well as with preventive anti-infectious vaccines, antibodies and T- cell responses can be mobilized, the kinetics, size and dura- tion of these responses are very different. For example, when modern flow cytometry technologies allowed to quantify specific T-cell responses, it was found that cancer patients harbour anti-tumour antigen specific T- cells amounting around 0.01% of all T-cells, which expand to about 1-2% after vaccination [15]. These figures contrast with the huge expansion of specific T-cells in acute viral infections, which, at the peak level, can reach above 30% and more of all T-cells [16]. Also in the humoral branch of the immune response, specific B cells expand up to 50% of all clonable memory B cells following influenza vaccination [17]. Chronic infections create a more meaningful intermediate situation given by an exposure to replicating and non-self antigen which persists long time, allowing to explore what happens when the immune system is chronically stimulated by an antigen which cannot be eliminated [18,19]. Although specific mechanisms and kinetics vary among different persisting viruses, the emerging general picture is that after an initial expansion of the immune response oc-