UNIVERSITÀ DEGLI STUDI DI TORINO

MERAVAX – DNA VACCINE TO INCRESE THE ANTITUMOR IMMUNE RESPONSE

Modern oncology is based on the simple but at the same time innovative concept of “One health”, which recognizes the relevance of the similarities between diseases in humans and animals. In particular, tumors that develop spontaneously in dogs are extremely similar to human ones, both from a histological and molecular point of view, as well as for the clinical behaviour. Therefore, canine patients represent an excellent translational model for the development of new effective anti-tumor therapies that could simultaneously revolutionize the veterinary and human clinic. In this panorama of comparative oncology research rises out our project.

Patent status

SUBMITTED

Priority Number

102015000088978

Priority Date

30/12/2015

License

INTERNATIONAL

Market

Initially the reference market for our product will be the veterinary one.
The owner and his dog suffering from MM or OSA are the final beneficiaries, as they will take advantage of our product which is proposed as a cutting-edge therapy able to offer a prolongation of canine patient's survival and a continuous specialized support. According to the latest Eurispes statistics, the number of dogs living in our homes in Italy is about 7.000.000, while in Europe about 60.000.000. In Italy and Europe, the incidence of malignant tumors in dogs is increasing and more and more owners are willing to invest in cutting-edge care for their pets. In Italy it is estimated that there are more than 1,000 cases of canine patients suffering from MM and about 700 suffering from OSA per year, while they increase to about 8,500 and 4,000 respectively in Europe.
Furthermore, the application of our product could be extended to the treatment of other tumors than MM and OSA and its application could be evaluated not only in therapy (for oncological dogs), but also in prevention (for all dogs at an early age).
Another main target for the distribution / use of our product will be the veterinary oncology clinics (about 7.000 in Italy and over 70.000 in Europe) and the veterinarians themselves. There are about 30.000 veterinarians in Italy and over 240.000 in Europe registered in the official registers. From our survey, 95% of veterinarian oncologists would agree to offer our product to the owners. Finally, it is interesting to note that according to Euromonitor International, the pet market (considering not only pet-food but also all products and accessories for animals) at a global level is worth 90 billion euros. In the last 5 years, the pet market has therefore grown by 10%, of which 50% is attributable to the canine species.

Problem

Canine MM and OSA are two of the most interesting tumors in the comparative oncology field, as they have numerous similarities with the corresponding human tumor. In fact, both MM and OSA in dogs, in a completely similar way to what happens in humans, represent highly metastatic tumors and are resistant to conventional therapies.
In particular, the standard treatment for dogs suffering from MM and OSA, as for humans, is represented by surgical resection of the tumor, by radio- and chemo-therapy, with serious collateral effects and with a survival rate of a year that does not exceed 30% due to recurrences and metastases. It is therefore necessary to develop new therapeutic strategies for the treatment of these canine patients, and this could provide highly predictive results of tumor behaviour and clinical response to therapy even in human patients.

Limits of current technologies/ solutions

In the veterinary practice, conventional therapies available for the treatment of MM and OSA include surgical resection of the tumor in combination with adjuvant radiotherapy / chemotherapy with severe collateral effects and poor clinical efficacy. In this context, immunotherapy is emerging as a possible alternative solution. Some pilot studies in this area have been conducted by research groups and pharmaceutical companies, mainly from U.S. (Aratana Therapeutics, Pfizer, Zoetis, Merial). Currently for canine MM patients, the only immunotherapeutic strategy approved in the U.S. is ONCEPT (Merial), a DNA vaccine against the tyrosinase whose clinical efficacy is highly controversial and which has not obtained the approval in Europe. Regarding OSA canine patients, recently a vaccine called ADXS31-164, based on Listeria monocytogenes expressing the Her2 antigen, has obtained conditional approval for use in the veterinary clinic in the U.S. In this case collateral effects have emerged and this therapy is not available in Europe to date.

Killer Application

The initial idea is to propose the HuDo-CSPG4 vaccine as an adjuvant for the treatment of dogs with MM and OSA, but in the future it could be used for the prevention of tumor onset through the immunization of all young dogs. Furthermore, thanks to the strong translational power of canine models and to the human / dog hybrid structure of our vaccine, the results obtained in the veterinary field will provide a solid preclinical basis for the rapid evaluation of this immunotherapeutic strategy in a human clinical setting. Thanks to the wide expression of CSPG4 also in other types of tumors, still difficult to treat today, this vaccine could be extended for the treatment of numerous other neoplastic diseases, other than MM and OSA, in both dogs and humans.

Technology and our proposal

Our proposal is the development of an immunotherapeutic strategy directed against the CSPG4 molecule, to specifically and long-lastingly stimulate the patients' immune system to kill their own cancer cells in order to prevent recurrences and metastases, prolonging the survival. From our studies, the CSPG4 protein has emerged as an ideal immunotherapeutic target in these neoplasms as it plays a key role in tumor progression and is highly expressed on neoplastic cells but not on healthy tissues, making its immunological targeting safe. The product therefore consists of a chimeric human / dog DNA vaccine (HuDo-CSPG4) intended for the treatment of dogs affected by CSPG4-positive MM and OSA, extendable to the treatment of all tumors expressing this molecule. In particular, we propose to use HuDo-CSPG4 as a preventive or adjuvant vaccine, i.e. following resection and / or radiotherapy / chemotherapy of the primary tumor, for the prevention of recurrences and metastases, which represent the main cause of death. Its chimeric human / dog structure was designed to be able to break tolerance in canine patients against a "self" antigen such as CSPG4, but thanks to this hybrid sequence its application could also be extended to the treatment of CSPG4-positive human tumors.
The vaccination protocol foresee an intramuscular injection of the DNA plasmid, associated with electroporation using Cliniporator, an instrument already approved for human and veterinary clinics, to increase vaccine immunogenicity.

Advantages

In order for an anticancer vaccine to be safe, immunogenic, effective and have a wide range of application, the choice of the target antigen is of primary importance. Based on our studies, we have identified CSPG4 as the ideal target of DNA vaccination for the treatment of both MM and OSA, being highly expressed by both MM (approximately 60%) and OSA (approximately 80%) cells and on derived cancer stem cells, where it plays a key role in promoting tumor progression and resistance to therapy, while it is absent in healthy tissues. Furthermore, being a membrane receptor it is attackable both by antibodies and by the cell-mediated response induced by the vaccine. Our pilot veterinary clinical studies have demonstrated the safety and immunogenicity of vaccination with HuDo-CSPG4 in companion dogs with MM, increasing their one-year survival from 36%, in case of using only conventional therapies, to 80%, improving canine patient's quality of life.
In summary, the chimeric vaccine HuDo-CSPG4 represents an innovative and advantageous immunotherapy both from a clinical point of view for its safety and potential efficacy, and for its adaptability to the treatment of multiple tumor histotypes beyond MM, such as OSA and other CSPG4-positive tumors, both for its high translational potential from the veterinary to the human setting thanks to the chimeric structure, and finally from the economic point of view as regards the simplicity of large-scale production of the vaccine.

Roadmap

The final goal of the project is to propose HuDo-CSPG4 on the veterinary market as an adjuvant DNA vaccine for the treatment of MM and OSA and to obtain the preclinical data needed to extend its evaluation also in human clinical trials. To achieve this goal, the following milestones are expected.
Milestone 1- Evaluation of the stability of the chimeric HuDo-CSPG4 plasmid. DNA plasmids represent interesting vectors for anti-tumor vaccination because their production is simple and cheap and their structure is considered stable. We expect to confirm the stability of the HuDo-CSPG4 vaccine, to define the best long-term storage modalities to ensure a safe and easy large-scale distribution for multicentric clinical studies.
Milestone 2- Evaluation of the immunogenicity of the chimeric HuDo-CSPG4 vaccine. In order for a vaccination to have an effective antineoplastic potential, it must be capable of inducing a strong and specific immunological response against the tumor antigen, which we intend to characterize in vaccinated MM and OSA canine patients.
Milestone 3- Safety and clinical potential of the chimeric HuDo-CSPG4 vaccine in canine patients affected by MM and OSA. Based on our previous veterinary studies, no local or systemic side effects are expected. Clinical data from vaccinated or control canine patients will be collected to generate survival curves. These results will be essential to confirm the safety and the clinical potential of HuDo-CSPG4 DNA vaccination for the treatment of both canine MM and OSA.
Milestone 4- Evaluation of the translational power of the chimeric HuDo-CSPG4 vaccine in a human setting. The potential application of the chimeric HuDo-CSPG4 plasmid and its efficacy to induce an immunogenic response in a human clinical context will be evaluated through the development of in vitro assays defined as "human surrogates".

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