THERAPEUTIC VACCINATION WITH VACCIMEL IN THE ADJUVANT TREATMENT OF CUTANEOUS MELANOMA INCREASES DISTANT METASTASES FREE SURVIVAL, GENERATES LYMPHOCYTE CLONES REACTIVE AGAINST TUMOR ASSOCIATED ANTIGENS AND IS COMPATIBLE WITH FURTHER IMMUNOTHERAPEUTIC TREATMENT

The CSF470 vaccine (hereafter Vaccimel) with BCG and GM-CSF as adjuvants has been tried in cutaneous melanoma patients. In the adjuvant, randomized Phase II study CASVAC-0401, its efficacy was compared to IFN alpha2b. The endpoint was distant-metastases-free survival (DMFS). Vaccinated patients had longer DMFS than those treated with IFN alfa 2b. Purpose: Five years after locking the data for the Phase II study, an actualization of the clinical results was performed. Another analysis of DMFS was also performed on all the patients who have been treated with Vaccimel and were evaluated as a single cohort. The feasibility of combining Vaccimel with anti-immune check points inhibitors and targeted chemotherapy was analyzed, especially due to the presence of BCG in the vaccine treatment. A patient with in transit metastases was analyzed in detail, to produce a proof of concept. Methods: Actualization of patient's status was carried out through a revision of clinical data. Kaplan Meier curves and statistical methods were used to analyze and compare the data obtained with other studies. RNA seq and immunohistochemistry were performed on a single biopsy obtained 10 years after patient 5 entered the clinical study. Results: The benefit in DMFS in the CASVAC-0401 study was maintained in the vaccinated group versus the IFN alfa2b treated group (p=0.035) with a median DMFS of 96 months for Vaccimel and 13 months for IFN alfa2b. When a single cohort of Vaccimel-treated patients stages IIB, IIC and III (n=30) was analyzed , the median DMFS was 150 months. The DMFS value at 48 months follow up was 65 %, which was not statistically different from DMFS values obtained with ipilimumab, pembrolizumab, nivolumab or dabrafenib/trametinib. Patient #5 has in-transit metastases and she has been previously randomized to the vaccine group. After completion of the study and disease progression, she was treated successively with vemurafenib, hyperthermic infusion , nivolumab, and dabrafenib/trametinib. During nine years, she underwent several cycles of complete responses followed by recurrences; previously administered BCG did not induce any untoward toxic effects in ulterior treatments. Conclusion: Vaccimel in conjunction with BCG and GM-CSF is an effective treatment in adjuvancy for cutaneous melanoma patients in stages IIB, IIC and III. Vaccination is compatible with subsequent treatments with ICKI Mabs and BCG contained does not add toxicity.