HER2/neu peptide-based vaccines, with GM-CSF as an adjuvant, in patients with advanced-stage HER2/neu-expressing cancers.

Rationale Despite advances in surgery, chemo­ merapy, and radiation, paciems wim solid mmors such as breast, ovarian, or lung cancer may relapse because of residual microscopic disease. The identification ofseveral tumor amigens, such as HER2! neu and p53, and an increased under­ standing of the role rhey play in malig­ nam cransformation, have led to clinical studies evaluaring antigen-specific' cancer V;lccines chat target biologically relevant proteins. l This approach holds meoretic promise for potential eradicatio n of residual subclinical disease through active . .. lmmuruzanon. The HER2/neu prmem is a rumor anti­ gen. It consiscs of a large cysteine-rich extraCellular domain (EeD) which prob­ ably funccions in ligand binding, a shorr transmembrane domain, and a small cytoplasmic domain ,,:,iili tyrosine kinase a.crivity. In some nonna! adult tissue cells, me HER2/neu gene is present as a single capy.l Amplificacion of the gene or over­ e..xpressiol1 by posnranscriptiol1al medl­ al1isms leads W overexpression of the associated p[Qrein and, rhus, plays a role in malignanr transformarion by con­ rriburing to the uncontrolled growm of cancer cells. HER2/ neu overexpression has been described in a variety of dif­ ferenc tumor types, including breast, ovarian, non-small-ce!llung, renal cd!, prost<ue, pancreas, colon, gastric, salivary, bladder, and oral squamous cell carcino­ mas. HER2/neu overexpression, in gen­ eral, is regarded as a poor prognostic factor. In addition, HER21 neu overex­ pression appears w be a prediccive factor ror resistance m some chemomerapeucic agencs)-G Studies from our laboratory and others have demonstrated that: some patients with HER2!nro-over=pressing cancers have existent antibody and T-cell re­ sponses to the protein. 7 In particular, patients with HER2/neu-overexpressing non-small-cell lung cancers can have a derecrable antibody immunity to HER1/ neu.S HER1!ne-u-specific cytoroxic T lymphocytes (CTL) have been identified in patienrs with a variety of HER11 neu­ overexpressing malignancies, including bteast, ovarian, and lung cancers. 911 Additionally, helper T-cell proliferation specific for the HER2lneu protein and selected peptide epitopes has been de­ tected in parienrs with HER2/neu-over­ expressing breast cancers. 12 Once HER2!neu nad been defined as a human rumor ancigen, an immuniza­ tion strategy ro augmenc immunity ill pa~iencs with a preexistent: immune response or co generate immunity in patients with no detectable HER2lmu