Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine

Abstract

Patients with metastatic melanoma were immunized with an immunodominant peptide derived from the gp100 melanoma-melanocyte differentiation Ag that was modified to increase binding to HLA-A+0201. A total of 10 of 11 patients who received the g209-2M peptide alone developed precursors reactive with the native g209 peptide, compared with only 5 of 16 patients who received g209-2M peptide plus IL-2 (p2 = 0.005). Peptide reactivity closely correlated with the recognition of HLA-A+0201 melanoma cells (p < 0. 001). The decrease in immune reactivity when peptide was administered with IL-2 appeared specific for the immunizing peptide, since reactivity to an influenza peptide resulting from prior exposure was not affected. Preexisting antitumor precursors did not decrease when peptide plus IL-2 was administered. The administration of GM-CSF or IL-12 also resulted in a decrease in circulating precursors compared with the administration of peptide alone, though not as great a decrease as that seen with IL-2. Immunization with peptide plus IL-2 did, however, appear to have clinical impact since 6 of the 16 patients (38%) that received peptide plus IL-2 had objective cancer regressions. It thus appeared possible that immunization with peptide plus IL-2 resulted in sequestering or apoptotic destruction of newly activated immune cells at the tumor site. These represent the first detailed studies of the impact of immunization with tumor peptides in conjunction with a variety of cytokines in patients with metastatic cancer.

FIGURE 1

Patients were immunized with g209–2M peptide in IFA either alone or with IL-2, IL-12, or GM-CSF, as described in the text. Each dot represents a single patient. PBMC were obtained after two immunizations and assayed for reactivity as assessed by IFN-γ secretion against the native g209 peptide and a control g280 peptide. Data are presented as the ratio of reactivity to g209 peptide compared with g280 peptide.

FIGURE 2

Patients were immunized with g209–2M peptide in IFA. Reactivity of PBMC from four patients were tested multiple times for specific reactivity against the g209 peptide and the HLA-A*0201 501 mel cell line. Reactivity against peptide and tumor as highly correlated (p < 0.001).