Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine

Abstract

Purpose: The availability of a variety of immune response modifiers creates an opportunity for improved efficacy of immunotherapy, but it also leads to uncertainty in how to combine agents and how to assess those combinations. We sought to assess the effect of the addition of granulocyte/macrophage colony-stimulating factor (GM-CSF) to vaccination with a melanoma vaccine.

Experimental design: Ninety-seven patients with resected melanoma (stage II-IV) were enrolled, stratified by stage, and randomized to receive a cellular melanoma vaccine with or without GM-CSF. The primary endpoint was delayed-type hypersensitivity (DTH) response to melanoma cells. Antibody responses, peripheral leukocyte counts, and survival were also examined.

Results: The GM-CSF arm showed enhanced antibody responses with an increase in IgM titer against the TA90 antigen and increased TA90 immune complexes. This arm also had diminished antimelanoma cell delayed-type hypersensitivity response. Peripheral blood leukocyte profiles showed increases in eosinophils and basophils with decreased monocytes in the GM-CSF arm. These immune changes were accompanied by an increase in early melanoma deaths and a trend toward worse survival with GM-CSF.

Conclusion: These data suggest that GM-CSF is not helpful as an immune adjuvant in this dose and schedule and raise concern that it may be harmful. Based on the discordant findings of an immune endpoint and clinical outcome, the use of such surrogate endpoints in selecting treatments for further evaluation must be done with a great deal of caution.

Figure 1

Delayed-type hypersensitivity (DTH) testing. Mean diameter of induration of each treatment group at baseline and during vaccination. * p<0.05 in exploratory T test for each timepoint.

Figure 2

Antibody response measures: A) Mean titer of anti-TA90 IgG, B) Mean titer of anti-TA90 IgG in the absence of adsorption with bovine serum albumen, C) mean titer of anti-TA90 IgM, D)Mean measure (OD: optical density) of TA90-IgG immune complex. * p<0.05, ** p=0.06 for T-test at each timepoint.

Figure 3

Mean peripheral blood counts of each treatment arm at the indicated time points. * p<0.05, ** p=0.06 for T-test at each time point.

Figure 4

Kaplan-Meier plot of overall survival of the GM-CSF (black) and non-GM-CSF (gray) arms. Logrank test demonstrated a significant difference when examined at two years, but with additional follow up this difference is now a trend, p=0.097.