A pilot clinical trial testing mutant von Hippel-Lindau peptide as a novel immune therapy in metastatic renal cell carcinoma

Abstract

Background: Due to the lack of specific tumor antigens, the majority of tested cancer vaccines for renal cell carcinoma (RCC) are based on tumor cell lysate. The identification of the von Hippel-Lindau (VHL) gene mutations in RCC patients provided the potential for developing a novel targeted vaccine for RCC. In this pilot study, we tested the feasibility of vaccinating advanced RCC patients with the corresponding mutant VHL peptides.

Methods: Six patients with advanced RCC and mutated VHL genes were vaccinated with the relevant VHL peptides. Patients were injected with the peptide mixed with Montanide subcutaneously (SQ) every 4 weeks until disease progression or until the utilization of all available peptide stock.

Results: Four out of five evaluable patients (80%) generated specific immune responses against the corresponding mutant VHL peptides. The vaccine was well tolerated. No grade III or IV toxicities occurred. The median overall survival (OS) and median progression-free survival (PFS) were 30.5 and 6.5 months, respectively.

Conclusions: The vaccine demonstrated safety and proved efficacy in generating specific immune response to the mutant VHL peptide. Despite the fact that the preparation of these custom-made vaccines is time consuming, the utilization of VHL as a vaccine target presents a promising approach because of the lack of other specific targets for RCC. Accordingly, developing mutant VHL peptides as vaccines for RCC warrants further investigation in larger trials.

Trial registration: 98C0139.

Figure 1

Immune responses measured by ELISPOT assay. ELISPOT results for all patients who had positive immune responses to the corresponding VHL peptide (spots/10⁶ PBMC) in purple compared with the control peptide (TAX) in red: patient 2 (panel A); patient 6 (panel C); patient 3 (panel B); and patient 4 (panel D). Pre = prevaccination sample; Post V = postvaccination sample marked by the vaccine number; and F/u = follow up sample marked in months (ms) from the last post vaccine sample.

Figure 2

Regulatory T cells (T regs). The percentage of T regulatory cells (CD4⁺CD25⁺FoxP3⁺) measured in the peripheral blood of the evaluable patients (patient 2, 3, 4, 5, and 6) pre and postvaccination. The postvaccination samples were taken during the last vaccination visit for every patient except patient 3 whom the last available T regs sample was during vaccination 5.