4170 - Anti-CSPG4 DNA vaccination as a promising strategy for the treatment of CSPG4+ tumors: a comparative oncology trial

Background

Among the most interesting targets for immunotherapeutic approaches, the Chondroitin Sulfate Proteoglycan (CSPG)4 stands out, with low expression in healthy tissues, high expression in several solid tumors and a key role in cancer progression. Because of the translational power of dogs as pre-clinical models for human malignancies and the CSPG4 over-expression by both human and canine malignant melanoma (MM), we demonstrated the safety and the clinical effectiveness of a xenogeneic human (Hu)-CSPG4 DNA vaccine in client-owned canine patients with stage II-III surgically resected CSPG4⁺ MM. However, Hu-CSPG4 vaccine was barely effective in activating human T cells from healthy donors in vitro. Based on these results, we aimed to increase the translational power of our approach and to extend it for the treatment of CSPG4⁺ tumors other than MM.

Methods

We generated a hybrid plasmid, derived in part from the Hu- and in part from the dog (Do)-CSPG4 sequences (HuDo-CSPG4). We tested the safety, immunogenicity and anti-tumor potential of HuDo-CSPG4 DNA vaccine in mice, in dogs with stage II-IV surgically resected CSPG4⁺ MM and in a human setting in vitro. We evaluated the potential of CSPG4-immune-targeting also for osteosarcoma (OSA).

Results

Chimeric HuDo-CSPG4 vaccination is strongly immunogenic in mice. In canine patients, the procedure is safe and induces antibodies (Ab) against both Hu- and Do-CSPG4, with a higher affinity and anti-tumor potential as compared to Hu-CSPG4. Clinically, HuDo-CSPG4 is effective in increasing the overall survival of vaccinated canine MM patients as compared to controls. Data obtained in vitro with T cells from human healthy donors suggest HuDo-CSPG4 is more immunogenic than Hu-CSPG4. Moreover, CSPG4 over-expression was demonstrated in human and canine OSA. Interestingly, anti-CSPG4 specific monoclonal Ab and sera derived from CSPG4 vaccinated canine MM patients showed to significantly inhibit human and canine CSPG4⁺ OSA cell proliferation, migration and osteospheres generation.

Conclusions

These results provide the rationale to propose HuDo-CSPG4 vaccination for the treatment of canine CSPG4⁺ tumors, to be successfully translated in a human setting.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Federica Cavallo.

Funding

Associazione Italiana per la Ricerca sul Cancro (AIRC), Italian Ministry of Health.

Disclosure

All authors have declared no conflicts of interest.