Preclinical vaccines against mammary carcinoma

Abstract

Vaccines against human breast cancer are an unfulfilled promise. Despite decades of promising preclinical and clinical research, no vaccine is currently available for breast cancer patients. Preclinical research has much to do with this failure, as early mouse models of mammary carcinoma did not mirror the molecular, cellular, antigenic and immunological features of human breast cancer. The advent of HER-2 transgenic mice gave impulse to a new generation of cell and DNA vaccines against mammary carcinoma, that in turn led to the definition of significant antigenic (oncoantigens) and cellular (cancer-initiating cells, preneoplastic lesions, incipient metastases) targets. Future preclinical developments will include the discovery of novel oncoantigens in HER-2-negative mammary carcinoma and the targeting of activated HER-2 molecular variants. Translation to clinically effective vaccines will be fostered not only by new preclinical model systems, but also by the possibility to conduct veterinary vaccination trials in companion animals.

Keywords::

• cancer immunoprevention
• cell vaccines
• companion animals
• DNA vaccines
• genetically-modified mice
• HER-2
• oncoantigens
• translational oncology
• veterinary trials

Financial & competing interests disclosure

The work of the authors is supported by grants from the Italian Association for Cancer Research (AIRC; IG 11675 to F Cavallo; IG 10353 to PL Lollini), the Italian Ministry for the Universities and Research, the Fondazione Ricerca Molinette Onlus, the University of Turin and the Compagnia di San Paolo (Progetti di Ricerca Ateneo/CSP). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • There is no approved vaccine for human breast cancer, despite decades of research. Early mouse models of mammary carcinoma, which do not mirror the immunology of human breast cancer, hampered the development of effective vaccines.

• • The advent of HER-2 transgenic mice fostered the design of a novel generation of powerful anti-HER-2 vaccines, and led to the development of novel concepts in tumor immunity.

• • Different vaccine technologies, designs and protocols yielded excellent protection from HER-2-positive mammary carcinoma in mice. DNA vaccination emerged as an eminently flexible and translatable technology.

• • Highly immunodeficient mice reconstituted with a human immune system can be used to test vaccines against human tumors, however current models do not reconstitute the complexity of human tumor immunology.

• • Oncoantigens are defined as tumor antigens causally involved in tumor onset and malignancy. Oncoantigens are optimal vaccine targets for the prevention of tumor onset and metastasis development.

• • HER-2 is the prototypical oncoantigen of mammary carcinoma. The definition of search strategies, combining preclinical and clinical systems, is leading to the discovery of oncoantigens in mammary carcinomas lacking HER-2 overexpression.

• • Activated HER-2 isoforms expressed in human breast cancer are a promising target for the development of novel vaccines.

• • Preclinical development of innovative vaccines will find an optimal environment in novel genetically modified mice and in veterinary trials in companion animals.