Safety and immunologic response of a viral vaccine to prostate-specific antigen in combination with radiation therapy when metronomic-dose interleukin 2 is used as an adjuvant

Abstract

Purpose: We have previously reported on the safety and immunologic response of a poxvirus-based vaccine encoding prostate-specific antigen (PSA) used in combination with radiation therapy in patients with localized prostate cancer. We hypothesized that a "metronomic" dose of interleukin 2 (IL-2) as a biological adjuvant would cause less toxicity while maintaining immunologic response.

Experimental design: Eighteen patients with localized prostate cancer were treated in a single-arm trial using previously established doses of vaccine and radiation therapy. The vaccine used was a recombinant vaccinia virus engineered to encode PSA admixed with a recombinant vaccinia encoding the costimulatory molecule B7.1, followed by booster vaccinations with a recombinant fowlpox vector expressing PSA. Patients received a total of eight planned vaccination cycles, once every 4 weeks, with granulocyte-macrophage colony-stimulating factor given on days 1 to 4 and interleukin 2 (IL-2) at a dose of 0.6 MIU/M2 given from days 8 to 21 after each vaccination. Definitive external beam radiation therapy was initiated after the third vaccination cycle. Patients were evaluated for safety and immunologic response. Toxicity and immunologic activity were compared with the previously reported regimen containing a higher dose of IL-2.

Results: Seventeen of 18 patients received all eight cycles of vaccine with IL-2. Five of eight HLA-A2+ patients evaluated had an increase in PSA-specific T cells of > or =3-fold. Toxicities were generally mild, with only seven vaccination cycles of 140 given resulting in grade 3 toxicities possibly attributable to IL-2.

Conclusions: Metronomic-dose IL-2 in combination with vaccine and radiation therapy is safe, can induce prostate-specific immune responses, and has immunologic activity similar to low-dose IL-2, with markedly reduced toxicities.

Figures

Figure 1

A representative flow cytometry plot of Tregs and NK cells in peripheral blood of prostate cancer patients. A. Levels of CD4+CD25highFoxP3+ Tregs in the peripheral blood of a prostate cancer patient enrolled in metronomic dose IL-2. PBMCs were analyzed by flow cytometry after cell surface labeling with PerCP-Cy5.5-conjugated anti-CD4, phycoerythrin (PE)-conjugated anti-CD25 and intracellular staining with FITC-conjugated anti-FoxP3. Levels of CD4+CD25highFoxP3+ Tregs are presented as a percentage of total CD4+ T cells. B. Levels of NK cells in the peripheral blood of a prostate cancer patient enrolled in “standard” dose IL-2 cohort. PBMCs were analyzed by flow cytometry after cell surface labeling with phycoerythrin (PE)-conjugated anti-CD3 and FITC-conjugated anti-CD56. Levels of NK cells (CD3-CD56+) are presented as a percentage of total PBMCs.