Among the various forms of cancer, non-small cell lung cancer is the most frequently diagnosed and the leading cause of deaths. CIMAvax-EGF has been introduced as a first-of-its-kind EGF immune-depleting therapy and shows promise for improvement of the survival rate and quality of life of patients with NSCLC. As part of the continued development of this vaccine, it is of paramount importance to attain long-term treatment. In this work, we have used hydroxyapatite nanoparticles (a biocompatible and biodegradable material) with an average size of 60 ± 10 nm to induce an anti-EGF immune response. Three candidates referred to as HANp–rhEGF–rP64k, HANp-MC, and HANp-IP were obtained through covalent interactions between proteins and nanoparticles. The total anti-EGF IgG titers induced by the three nanoparticulate systems in mice were between 1:5000 and 1:10,000 during all periods of study (4 immunization doses and 3 extractions, 104 days). No differences in the IgG2/IgG1 ratio were observed in comparison to CIMAvax-EGF, with both being consistent with a Th2 polarization pattern. Histological evaluation of muscle tissues showed that the new nanoparticulate systems do not affect the injection sites in mice. Finally, a study of immune response induction with CIMAvax-EGF and maintenance with HANp–rhEGF–rP64k demonstrated that it is possible to maintain the immune response over the course of treatment (91 days). These results introduce these new hydroxyapatite nanoparticulate systems as effective candidates for the long-term treatment of lung and other cancers of epithelial origin.