Adenovirus Delivered B7 in Breast Cancer Immunotherapy

Lee, William

Abstract

T cell co-stimulation provided by B7 molecules on the surface of professional antigen presenting cells is essential for allowing antigens to stimulate T cell proliferation and a productive immune response; antigen stimulation in the absence of B7 co-stimulation induces T cell clonal anergy. Elucidation of B7's importance has allowed the design of rational strategies for enhancing the immunogenicity of tumor cells. Murine tumor cells engineered to express B7 ectopically induce an antitumor immune response that can reject established disease. These studies lead one to hypothesize that the immunogenicity of human breast cancer cell antigens may be enhanced to therapeutic benefit by ectopic expression of B7. Clinical application of this immunotherapeutic strategy is hindered by difficulties in delivering genes into primary human breast cancer cells which are difficult to grow in vitro. Recent work suggests that these problems can be overcome with use of recombinant adenovirus vectors. A Breast Cancer Treatment Group has been formed from collaborating investigators at the University of Pennsylvania and the University of Michigan to bring the concept of a B7-enhanced breast cancer cell vaccine to Phase I/II clinical trial. Its goals are to develop a recombinant adenovirus vector bearing a human B7 cDNA (AdhB7) and breast cancer cell isolation procedures to efficiently engineer primary human breast cancer cells to express B7. These reagents and procedures will be used in breast cancer clinical trials that test the toxicity and efficacy of vaccines made of autologous tumor cells expressing ectopic B7. Three interactive programs make up this concerted effort: Program 1 is a laboratory program that will develop and test the efficacy and safety of the adenovirus vector that will be used to deliver and express the human B7 cDNA in human breast cancer cells. In vitro methods to monitor the development of T cell responses to tumor cell antigens and adenoviral antigens will be developed as part of this program. Program 2 is a laboratory program that will develop optimum methods for the isolation, purification, short-term in vitro maintenance and cryopreservation of human breast cancer cells. Program 3 is the clinical program that will design and execute Phase I/II clinical trials testing the vaccines made from autologous cancer cells and the vector and procedures developed in Programs 1 and 2. Monitoring of immune responses induced by this vaccine will use the methods developed in Program 1.