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Synthetic peptide vaccines targeting B-cell epitopes of the extracellular domain of the HER-2 oncoprotein were evaluated for their capacity to elicit HER-2-specific antibodies with antiproliferative activity. Several HER-2 B-cell epitopes were identified by computer-aided analysis of protein antigenicity, and selected B-cell epitopes were synthesized colinearly with a promiscuous T-helper epitope (208-302) derived from the measles virus fusion protein at either the NH2 or COOH terminus linked via a four-residue turn sequence (GPSL). In addition, one epitope sequence, 628-647, was mutated to optimize disulfide pairing to mimic the native HER-2 receptor. All of the four selected epitopes elicited high-titered antibodies in outbred rabbits with exceptionally high titers for MVF-HER-2(628-647). These antibodies were cross-reactive with the native HER-2 receptor. Antibodies elicited by MVF HER-2(628-647) inhibited proliferation of human HER-2-overexpressing breast cancer cells in vitro and caused their antibody-dependent cell-mediated cytotoxicity. Furthermore, immunization with MVF-HER-2(628-647) prevented the spontaneous development of HER-2/neu-overexpressing mammary tumors in 83% of transgenic mice. The engineered, chimeric peptide B-cell immunogen MVF-HER-2(628-647) may have applications in the prevention of HER-2-overexpressing cancers.

The clinical and immunological effects of a vaccine consisting of CTP37, a synthetic peptide corresponding to the COOH-terminal peptide (CTP) of beta-human chorionic gonadotropin (beta-hCG) conjugated to diphtheria toxoid, combined with CRL 1005, a novel synthetic nonionic block copolymer adjuvant, were examined. Twenty-one patients with metastatic, nontrophoblastic cancers received up to four immunizations by i.m. injection of a fixed dose of CTP37 and escalating doses of CRL 1005. Doses of CRL 1005 adjuvant as high as 75 mg were administered with 1 mg of CTP37 without evidence of significant local or systemic toxicity. Immunizations resulted in the production of IgG antibody to beta-hCG. CRL 1005 doses of 3-25 mg appeared to be optimal for antibody induction. Immunizations also resulted in increases in the cellular response of peripheral blood mononuclear cells (PBMCs) to the unconjugated CTP, hCG, and diphtheria toxoid. Responding PBMCs specifically secreted the TH1-associated cytokines IFN-gamma and interleukin (IL)-2 as well as the TH2-associated IL-5 and IL-10. Increased expression of IFN gamma and IL-5 mRNAs by PBMCs 4 h after immunization was also observed. CRL 1005 administered with CTP37 in aqueous solution is well tolerated. The CTP37-CRL 1005 subunit vaccine has the capacity to stimulate potentially beneficial humoral and cellular immune responses in patients with advanced cancer.

Mean 24-hr growth hormone, luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone concentrations determined preoperatively in 16 women with benign breast masses and 17 patients with breast cancer were similar to those levels found in 25 age- and weight-matched control subjects. Mean 24-hr testosterone levels, however, were significantly elevated in women with breast cancer evaluated in the luteal phase of their cycles and were normal in postmenopausal breast cancer women. In addition, serum thyroid-stimulating hormone, thyroxine, cholesterol, and triglyceride levels were normal in these subjects. Plasma cortisols and urinary 17-hydroxysteroid excretion tended to be higher in both the benign and malignant breast disease group and probably reflected preoperative anxiety. Hence, we have found normal concentrations of a variety of endocrine and other biochemical agents that can stimulate breast tissue growth and/or have been previously reported to be disordered in women with breast cancer.

Mean 24-hr prolactin concentrations were determined in 25 female control subjects, 16 women with benign breast masses, and 23 subjects with breast cancer. This evaluation performed before breast surgery revealed significantly decreased (p less than 0.02) nocturnal (12 a.m. to 7 a.m.) prolactin concentrations in 12 postmenopausal breast cancer subjects that contrasted with significantly increased (p less than 0.05) nocturnal prolactin levels in five luteal-phase premenopausal women with breast cancers. Prolactin concentrations in patients with benign breast disease were not significantly different from control subjects. Two of the premenopausal breast cancer patients had marked preoperative elevations in their mean 24-hr prolactin levels, and they were two of the three subjects who have since expired. Nocturnal prolactin secretion was significantly decreased (p less than 0.03) in four premenopausal breast cancer patients when they were studied 1 year after surgery; however, it remained the same in the eight postmenopausal breast cancer patients similarly evaluated. Although disordered prolactin regulation has been found in these women with breast cancer, its role in the etiology and progression of human cancer is still uncertain.