Phase I Active Immunotherapy With Combination of Two Chimeric, Human Epidermal Growth Factor Receptor 2, B-Cell Epitopes Fused to a Promiscuous T-Cell Epitope in Patients With Metastatic and/or Recurrent Solid Tumors

Abstract

A B S T R A C T PurposeTo evaluate the maximum-tolerated dose (MTD), safety profile, and immunogenicity of two chimeric, B-cell epitopes derived from the human epidermal growth factor receptor (HER2) extracellular domain in a combination vaccine with a promiscuous T-cell epitope (ie, MVF) and nor-muramyl-dipeptide as adjuvant emulsified in SEPPIC ISA 720. Patients and MethodsEligible patients with metastatic and/or recurrent solid tumors received three inoculations on days 1, 22, and 43 at doses of total peptide that ranged from 0.5 to 3.0 mg. Immunogenicity was evaluated by enzyme-linked immunosorbent assay, flow cytometry, and HER2 signaling assays. ResultsTwenty-four patients received three inoculations at the intended dose levels, which elicited antibodies able to recognize native HER2 receptor and inhibited both the proliferation of HER2-expressing cell lines and phosphorylation of the HER2 protein. The MTD was determined to be the highest dose level of 3.0 mg of the combination vaccine. There was a significant increase from dose level 1 (0.5 mg) to dose level 4 (3.0 mg) in HER2-specific antibodies. Four patients (one each with adrenal, colon, ovarian, and squamous cell carcinoma of unknown primary) were judged to have stable disease; two patients (one each with endometrial and ovarian cancer) had partial responses; and 11 patients had progressive disease. Patients with stable disease received 6-month boosts, and one patient received a 20-month boost. ConclusionThe combination vaccines were safe and effective in eliciting antibody responses in a subset of patients (62.5%) and were associated with no serious adverse events, autoimmune disease, or cardiotoxicity. There was preliminary evidence of clinical activity in several patients.

Insulin-Like Growth Factor-1 Receptor Signaling Increases the Invasive Potential of Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer Cells via Src-Focal Adhesion Kinase and Forkhead Box Protein M1

“…The ADCC assay was performed as previously described (Kaumaya et al, 2009) using effector peripheral blood mononucleated cells, which were obtained from normal human donors and isolated by density-gradient centrifugation in Ficoll-Hypaque (Pharmacia Biotech, Piscataway, NJ). The cells were washed twice in RPMI 1640 with 5% fetal calf serum and then serially diluted in 96-well plates to give effector/target ratios of 100:1, 20:1, and 4:1.…”

IGF-1R peptide vaccines/mimics inhibit the growth of BxPC3 and JIMT-1 cancer cells and exhibit synergistic antitumor effects with HER-1 and HER-2 peptides

“…using a bioluminescence cytotoxicity assay kit (aCella-TOX TM ), as previously described. 38 We found that cancer cell lysis was, indeed, significantly increased following treatment with our vaccine antibodies. The effects increased as the effector to target cell ratio increased, with the greatest effects being achieved at an effector to target cell ratio of 100:1, as shown in Figure 5.…”

“…62 We further validated combinatorial therapies targetingHER-2 and VEGF, 63 and demonstrated that immunotherapy with HER-2 and VEGF peptide mimics plus metronomic paclitaxel elicited superior anti-neoplastic effects in transplantable and transgenic mouse models of human breast cancer. 29 We recently translated our vaccine studies into a phase 1 clinical trial 38 and are presently conducting a new FDA-approved, NCIfunded phase 1/11b trial (NCT01376505) with an improved vaccine combination. These strategies possess the combined advantages of inhibiting multiple distinct receptors (HER-1:HER-2; HER-2:HER-2; and HER-2: HER3) to potentially overcome mechanisms of resistance to conventional HER-targeted therapies.…”

“…The ADCC assay was performed basically as previously described 38 using effector PBMCs derived from normal human donors and enriched using density-gradient centrifugation in Ficoll-Hypaque (Pharmacia Biotech, Piscataway, NJ). The cells were washed twice in RPMI 1640 with 5% FCS and then serially diluted in 96-well plates to give effector to target ratios of 100:1, 10:1, and 4:1.…”

HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium

“…Much of the preclinical work was performed in HER2/neu transgenic mouse models due, in part, to the fact that a murine homolog was not confirmed until the early 2000s [14][15][16], although other models were also employed (dog, guinea pig, rat, primate) [209][210][211][212][213][214]. The majority of these have focused on the extracellular domain of HER2/neu due, in large part to the high degree of homology of the intracellular kinase domain with other receptor tyrosine kinases both in and outside of the HER family [209,[215][216][217][218][219], although some strategies have included elements from the intracellular domain [213][214][215]. Indeed, cytotoxic T-lymphocytes directed against HER2/neu have been documented to react with HER3 and HER4 [220].…”