Anaplastic Lymphoma Kinase (ALK) pre-birth immunotargeting counteracts tumor growth in neuroblastoma-prone offspring

Neuroblastoma (NB) is the most common malignancy diagnosed in the first year of life. The low rate of response to standard treatments observed in patients suffering high-risk NB, often associated with the activating mutations of the Anaplastic Lymphoma Kinase (ALK) and the amplification of MYCN oncogene, requires the development of new preventive and therapeutic strategies. Since NB may originate during early embryogenesis, a pre-birth immunotherapy-based intervention could represent a promising approach. Here, we evaluated the effect of a pre-birth DNA immunization against ALK (ALK-PBDI) in a mouse model recapitulating high-risk NB features, the MYCN/ALKF1174L -transgenic mice. To this aim, ALK-vaccinated MYCN-transgenic female mice were mated with ALKF1174L -transgenic males. A significantly delayed tumor growth coupled with enhanced overall survival were observed in MYCN/ALKF1174L -transgenic offspring, compared to controls; comparable results were also obtained in a transplantable NB tumor model. The antitumor effect exerted by ALK-PBDI is associated with an ascertained passage of anti-ALK antibodies from mothers to the offspring and with the anti-ALK active immune response unleashed in the offspring as a consequence of the antigen transfer via immunocomplexes. Interestingly, by evaluating the role of vaccine-induced anti-ALK antibodies on NB human cell lines, we demonstrated their ability to affect ALK expression and localization, as well as cell proliferation, migration and neurospheres formation. Overall, these results suggest that ALK-PBDI is an effective strategy in counteracting tumor growth in a mouse model of neonatal NB and that vaccine-induced anti-ALK antibodies may have a role in controlling NB growth and dissemination.