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Combination immunotherapy of established breast cancer
Tumor Cell Biology III
Background: Immunotherapy has considerable potential for the treatment of breast cancer given the use of monoclonal antibodies (mAbs) such as Herceptin. However, response rates using this therapy are low and often not complete and tumors relapse. It is our hypothesis that the immune system is not sufficiently activated by any of single treatment alone. There has been a revolution over the past 10 years in our knowledge regarding the cellular and molecular mechanisms of action of the immune system. Armed with this knowledge we have begun to examine the therapeutic effect of combining three mAbs (trimAb) enhancing distinct stages of the immune response against breast cancer. MAb anti-DR5 (specific for TRAIL-R) is used to initiate Stage 1 by inducing tumor cell apoptosis thereby providing a "danger" signal to alert the immune system and provides a ready source of tumor antigens. MAb anti-CD40 is used to augment the immune response at Stage 2 that involves the activation of dendritic cells. MAb anti-CD137 (4-1BB) is used to further augment the immune response at Stage 3 that involves the co-stimulation of T cell immunity. When established 25 mm2 subcutaneous 4T1 mouse mammary tumors were treated with the trimAb therapy, 70% of mice were cured. By contrast, any one or two mAbs were comparatively ineffective. Objective: To design an effective combined immunotherapy of established breast cancer. Aim 1: Preclinical evaluation of combined anti-DR5, anti-CD40 and anti-CD137 therapy of established breast cancers. Aim 2: Compare combined immunotherapies in a self-antigen model of established breast cancer. Study design: In Aim 1 we will evaluate trimAb therapy of established mouse breast cancers of various types and sizes. The mechanisms by which the combined therapy eradicates established tumors will be investigated. The ability of the therapy to create memory to the tumors will also be analysed. Escaping tumors will be evaluated for resistance and we will determine whether candidates anti-CTLA-4 or IL-21 can further improve trimAb therapy. In Aim 2, a defined self-antigen model of established breast cancer will be used in which we can evaluate the comparative efficacy of anti-erbB-2 (Herceptin) and anti-DR5 in initiating tumor immunity as well as testing the anti-tumor and autoimmune effects of the most optimal combined mAb therapy determined in Aim 1. Significance, Potential outcomes and benefits of the research: This rationally designed trimAb therapy enhancing multiple stages of the immune response is novel and the preliminary data are very exciting. The successful completion of Aim 1 will teach us how the therapy rejects most established breast tumors, why it sometimes fails, and how it may be further improved. The comparison of this new combined therapy with existing approaches in a new model derived in Aim 2 will be of great benefit to future design of immunotherapies. We anticipate that the proposed studies will produce a clearer picture of what is required to induce an effective immune response against established breast tumors, and bring us closer to using the same combination in patients afflicted by breast cancer.
We propose to use the body's own immune system against established breast cancer. Recent advances in our understanding of immunity have made it clear that the many millions of white blood cells that make up the immune system work together in an interactive network to eliminate disease. However, when it comes to advanced breast cancer, this network often breaks down at some stage. The tools to trigger these stages of the immune system are hormones (cytokines) and antibodies, many of which have already been designed for safe injection into humans in early clinical trials. While none of these antibodies and cytokines alone is likely to eradicate an established breast cancer in patients, we believe we have discovered the key points in the immune network and now understand that by combining these antibodies and cytokines in a sequential treatment, we will begin to have very profound effects on established breast cancer. The innovative integrated therapy we wish to assess will rely on a combination of antibodies or cytokines that in sequence: (1) kill the cancer cells and attract immune cells to the tumor site; (2) stimulate and mature cells that pick up the tumor proteins and carry it back to the lymph organs to alert the immune system; (3) effectively stimulate the T cells that are extremely specific cellular weapons that target and destroy diseased tissue while leaving normal tissue unharmed; (4) prolong the size and life of the pool of memory T cells that can respond to a second or further challenge by the tumor. In preliminary experiments in mice we have shown that a combination of three such antibodies can eradicate established breast tumors in the majority of mice. Lesions up to a half a centimetre in diameter were cured in 70% of mice and the treatment also eradicated tumors that had spread from the primary lesion. By contrast, any one or two antibodies alone were comparatively ineffective. Based on these results we now wish to test this therapy in even more rigorous mouse models, examine how the therapy works and why some mice are not cured, and determine whether we can further improve the therapy by adding antibodies and cytokines that further boost immunity. We will also derive a new mouse model in which an existing antibody in the clinic for breast cancer, Herceptin, can be compared directly with these new approaches. Using these original and innovative approaches, our team is at the forefront of efforts to therapeutically boost the immune system against cancer. We anticipate that the proposed studies will lead to several possible new combination immunotherapies for treating more established breast cancer. The studies will also give us a clearer picture of the requirements for an effective response against tumor, and bring us closer to helping all those afflicted by breast cancer.