GP2 peptide vaccine(Cancer Insight LLC)

HER‐2/neu, overexpressed in breast cancer, is a source of immunogenic peptides that include GP2 and E75. Phase 2 testing of E75 as an adjuvant vaccine has suggested a clinical benefit. GP2, derived from the transmembrane portion of HER‐2/neu, has differing binding characteristics and may be more immunogenic than E75. Results of the first phase 1 trial of GP2 peptide vaccine are presented.

Disease‐free, lymph node‐negative, human leukocyte antigen (HLA)‐A2+ breast cancer patients were enrolled. This dose escalation trial included 4 groups to determine safety and optimal GP2 peptide/granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) dose. Toxicities were monitored. Immunologic response was assessed ex vivo via the HLA‐A2:immunoglobulin dimer assay to detect GP2‐specific CD8+ T cells (and E75‐specific CD8+ T cells to assess epitope spreading) and in vivo via delayed type hypersensitivity (DTH) reaction (medians/ranges).

Eighteen patients were enrolled. All toxicities were grade ≤2. Eight (88.9%) of 9 patients in the first 3 dose groups required GM‐CSF dose reductions for local reactions ≥100 mm or grade ≥2 systemic toxicity. GM‐CSF dose was reduced to 125 μg for the final dose group. All patients responded immunologically ex vivo (GP2‐specific CD8+ T cells from prevaccination to maximum, 0.4% [0.0%‐2.0%] to 1.1% [0.4%‐3.6%], P < .001) and in vivo (GP2 pre‐ to postvaccination DTH, 0 mm [0.0‐19.5 mm] to 27.5 mm [0.0‐114.5 mm, P < .001). E75‐specific CD8+ T cells also increased in response to GP2 from prevaccination to maximum (0.8% [0.0%‐2.41%] to 1.6% [0.86%‐3.72%], P < .001).

The GP2 peptide vaccine appears safe and well tolerated with minimal local/systemic toxicity. GP2 elicited HER‐2/neu–specific immune responses, including epitope spreading, in high‐risk, lymph node‐negative breast cancer patients. These findings support further investigation of the GP2 vaccine for the prevention of breast cancer recurrence. Cancer 2010. © 2010 American Cancer Society.

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic β-islet cells together with T cells expressing an LCMV-gp–specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.