) Recent preclinical studies in ovarian cancer and nonsmall cell lung cancer have identified the her2/neu gene product(p185) as a tumor-associated antigen that provokes HLA-A2-restricted CTL function. Studies in our laboratory and others have shown that p185 also serves as a shared tumor antigen for breast cancers that are HLA-A2-positive. Thus, the her2/neu gene product may serve as a target for immunotherapy strategies including immunization. The mere existence of a tumor-associated antigen, although necessary, may not be sufficient for eradication of tumor because of tumor-induced immune defects or inadequate antigen stimulation. Optimal T-cell activation requires two signals: an antigenic stimulus and a costimulatory event. Our preliminary data suggest that T-cell stimulation by HLA-A2-matched her2/neu positive tumor cells can be augmented by transfecting the gene for B7 (a costimulatory molecule) into the her2/neu-positive breast cancer cell line. This permits the tumor cell to deliver both the antigenic and costimulatory signals necessary for T-cell activation. We have included GM-CSF as an adjuvant because recent studies have shown that it facilitates local antigen presentation by promoting differentiation of appropriate precursors into dendritic cells. These cells express high levels of class I and class II MHC molecules as well as appropriate costimulatory molecules. We propose to perform a phase I trial in which HLA-A2+ women with metastatic breast cancer with will be vaccinated in the right thigh with an HLA-A2+, her2/neu+, allogeneic breast cancer cell line (MDAMB-23 1) that has been genetically modified to express human B7. Cohorts of patients will receive escalating doses of irradiated transfected cells in combination with GM-CSF or BCG as adjuvants. The contralateral thigh will receive no treatment or injection of GM-CSF or BCG without tumor cells. Patients will be monitored for toxicity of immunization and evidence of tumor regression during the phase IA portion of the study while the phase IB portion of the study will examine the immunologic changes that result from immunization. We will determine her2/neu-specific CTL precursor frequency and cytokine production in vaccine-draining lymph node and peripheral blood lymphocytes. Completion of this research agenda is expected to determine if antigen-specific CTL immune responses can be generated in patients with breast cancer. The potential benefits of such an effective immunization regimen for women with breast cancer are great. Improvements in adjuvant therapy or in the treatment of women with metastatic breast cancer would have an immediate impact on the public health. Since her2/neu is expressed on other epithelial cancers (ovarian nonsmall cell lung and prostate cancer) another important feature of this work is its potential for widespread use against other common malignancies.
| Dols, Annemieke; Meijer, Sybren L; Hu, Hong-Ming et al. (2003) Identification of tumor-specific antibodies in patients with breast cancer vaccinated with gene-modified allogeneic tumor cells. J Immunother 26:163-70 |
| Chu, Y; Hu, H M; Winter, H et al. (1999) Examining the immune response in sentinel lymph nodes of mice and men. Eur J Nucl Med 26:S50-3 |
