Eulogio Pimentel

Gonadotrophin releasing hormone-based vaccine, an effective candidate for prostate cancer and other hormone-sensitive neoplasms.

Prostate growth, development, functions, and neoplastic transformation is androgen dependent. Estrogens have similar effects in the ovary and breast. Previous studies using gonadotrophin releasing hormone (GnRH/LHRH) vaccines have shown the usefulness of immunization against this hormone in prostate (PC) and breast cancer (BC). We have synthesized a peptide mutated at position 6 and attached to the 830-844 tetanic toxoid (TT) helper T cell sequence in the same synthesis process. After repeated pig immunizations, we have demonstrated a vaccine that significantly decreased testes size (p < 0.001), prostate (p < 0.01), seminal vesicles (p < 0.01), and testosterone (T) castration [0.05 nM ml(-1) (p < 0. 01)]. Similar results were obtained in adult male and female healthy dogs and Macaca fascicularis models. These data indicate that this GnRHm1-TT vaccine is safe and able to induce significant tumor growth inhibition in the Dunning R3327-H rat androgen responsive prostate tumor model. In these rats, the immunization induced high anti-GnRH titers concomitant with T castration reduction (p < 0.01) in 90% of the animals tested. In addition, 70% of the responders exhibited tumor growth inhibition (p = 0.02) and a survival rate approximately three times longer that those of untreated rats. These data indicate that GnRHm1-TT vaccine may be a potential candidate in the treatment of PC, BC, and other hormone-dependent cancers.

Prostate Cancer Immunotherapy – Strategy with a Synthetic GnRH Based Vaccine Candidate

Previous studies with Gonadotropin Releasing Hormone (GnRH/LHRH) vaccines have demonstrated the usefulness of immunization against this hormone in prostate cancer. To this purpose, we generated the completely synthetic GnRHm1-TT peptide which has been validated in a proof of concept formulated together with Montanide ISA 51 adjuvant. Such vaccine preparation induced a significant anti-GnRH immune response and correspondingly reduced testosterone to castration levels and thus produce a biological response in hormonedependent tumors. As a novel strategy the GnRHm1-TT peptide has been also emulsified with the adjuvant combination Montanide ISA 51 and VSSP. The use of this candidate in healthy animal models showed a significant increase in the anti GnRH immune response in comparison with the previous candidates, including their advantages regarding prostate and its testicle atrophy. Moreover, the use of the GnRHm1-TT/Montanide ISA 51/VSSP vaccine candidate produced a significant inhibition of tumor growth in mice transplanted with hormone-sensitive murine tumor Shionogi SC-115. The development of a Phase I clinical trial in patients with advanced prostate cancer using GnRHm1-TT/Montanide/VSSP vaccine, demonstrated the safety of using this candidate in humans as well as the therapeutic elements which must be demonstrated more widely in future clinical trials.