An Update of Cutaneous Melanoma Patients Treated in Adjuvancy With the Allogeneic Melanoma Vaccine VACCIMEL and Presentation of a Selected Case Report With In-Transit Metastases

Abstract

The CSF-470 vaccine (VACCIMEL) plus BCG and GM-CSF as adjuvants has been assayed in cutaneous melanoma patients. In the adjuvant randomized Phase II study CASVAC-0401, vaccinated patients had longer distant metastasis-free survival (DMFS) than those treated with IFNα2b. Five years after locking the data, an actualization was performed. The benefit in DMFS was maintained in the vaccinated group versus the IFNα2b-treated group (p = 0.035), with a median DMFS of 96 months for VACCIMEL and 13 months for IFNα2b. The favorable risk-benefit ratio was maintained. DMFS was also analyzed as a single cohort in all the IIB, IIC, and III patients (n = 30) who had been treated with VACCIMEL. The median DMFS was 169 months, and at 48 months follow-up, it was 71.4%, which was not statistically different from DMFS of previously published results obtained in adjuvancy with ipilimumab, pembrolizumab, nivolumab, or dabrafenib/trametinib. The possible toxicity of combining VACCIMEL with anti-immune checkpoint inhibitors (ICKi) was analyzed, especially since VACCIMEL was co-adjuvated with BCG in every vaccination. A patient with in-transit metastases was studied to produce a proof of concept. During treatment with VACCIMEL, the patient developed T-cell clones reactive towards tumor-associated antigens. Three years after ending the VACCIMEL study, the patient progressed and was treated with ICKi. During ICKi treatment, the patient did not reveal any toxicity due to previous BCG treatment. When she recurred after a 4-year treatment with nivolumab, a biopsy was obtained and immunohistochemistry and RNA-seq were performed. The tumor maintained expression of tumor-associated antigens and HLA-I and immune infiltration, with immunoreactive and immunosuppressive features. VACCIMEL plus BCG and GM-CSF is an effective treatment in adjuvancy for stages IIB, IIC, and III cutaneous melanoma patients, and it is compatible with subsequent treatments with ICKi.

Keywords: immune checkpoint inhibitor (ICKi); Bacille Calmette-Guérin (BCG); VACCIMEL; adjuvancy; cutaneous melanoma (CM); therapeutic vaccine.

Figure 1

Clinical update of VACCIMEL-immunized patients. (A) DMFS follow-up of the CASVAC-0401 study patients as of 10/05/2021 (p = 0.035, Wilcoxon test). Arms: VACCIMEL (black) (n = 19); IFNα2b (red) (n = 11). (B) DMFS Kaplan–Meier and Cox-regression comparison of adjuvant treatments for CM patients. Treatments: Combined VACCIMEL-immunized patients from Phase I and II studies (black) (9, 10); dabrafenib (yellow) (28); ipilimumab (light blue) (27); nivolumab (blue) (5); pembrolizumab (red) (6). (C) Forest plot of hazard ratio comparison of DMFS of different treatments versus VACCIMEL.

Figure 2

Patient #5 case report. (A) Time course of the disease and treatments received. ITM biopsies analyzed are indicated with a green box. (B–E) Pictures of ITM on patient’s right leg: (B) relapse after ending vaccination protocol; (C) progression before nivolumab; (D) response after nivolumab 240 mg every 14 days for 1 year; (E) relapse after 4 years nivolumab, showing multiple red amelanotic 1- to 3-mm-wide tumors.

Figure 3

Patient #5 immune response to common melanoma antigens. (A) T-cell response induced by VACCIMEL to HLA-A0201-restricted peptides from shared melanoma-associated antigens detected by IFN-γ ELISPOT. Pre: blood extracted at the selection process; Post 1, Post 2, and Post 3: blood extracted 6, 12, and 25 months after protocol start. (B) Quantification of the spots normalized to 10⁵ PBMC (right panel). (C) PMEL, tyrosinase (TYR), SOX-2 and MAGE B2 antigens abundance in VACCIMEL as determined by RNA-Seq and normalized in TPM.

Figure 4

Comparative analysis of Patient#5 ITM immune populations. Immunostaining was performed as described under Methods on ITM biopsies obtained before VACCIMEL immunization, after VACCIMEL immunization, and following nivolumab treatment: (A–C) HLA class I; (D–F) TYR; (G–I) PMEL; (J–L) CD8; (M–O) CD11c; (P–R) CD68. Scale bars: (A–I) 50 µm; (J–O) 100 µm; (P–R) 200 µm.

Figure 5

Patient #5 ITM immune genes expression profiling. (A) Boxplot showing expression of immune genes grouped in multiple categories, as described under Methods. Heatmaps showing expression of selected genes: (B) HLA molecules, (C) immunosuppressive molecules; (D) immune checkpoints (receptors and ligands).