Twenty-five years ago the first targeted therapy for cancer was introduced. Unlike standard chemotherapy, which has toxicity to all dividing cells leading to the side effects of conventional chemotherapy, this therapy is an antibody, rituximab, which specifically targets a molecule on the surface of lymphoma tumor cells, CD20. Antibody therapy has limited side effects, maintains patients' quality of life, and allows patients to avoid entirely or at least delay the need for conventional, cytotoxic chemotherapy. Trastuzumab is an antibody targeting HER2 that is expressed on a subset of breast cancers. Though it similarly has revolutionized the field of breast cancer therapy, both rituximab and trastuzumab do not cure the majority of patients with lymphoma or breast cancer. Further, patients with metastatic breast cancer, who have received prior treatments, have a very low chance of responding to trastuzumab. This group of patients with advanced breast cancer has a poor quality of life and is often too ill to tolerate aggressive chemotherapy. The goal of our work is to identify novel therapies that are non-toxic and can be used in combination with trastuzumab to increase the likelihood of a response among patients with advanced disease and of a cure for newly diagnosed patients.

One of the main mechanisms by which antibodies, including trastuzumab, attack breast cancer is by activating the patient's own immune system to recognize and destroy the tumor. The immune cells which can attack the tumor with the antibody's help are known as natural killer (NK) cells. We believe we can improve the killing ability of the NK cells by giving patients a second antibody that stimulates the NK cell. This antibody recognizes a piece on the NK cell's surface known as CD137, which is only present when the NK cell is activated for instance when it is exposed to a tumor, such as HER2+ breast cancer, and an antibody, such as trastuzumab.

To support our theory, we will demonstrate that CD137 is increased after NK cells come into contact with HER2+ breast cancer and trastuzumab both in culture and in patients receiving trastuzumab therapy. Next we will show that NK cells kill more breast cancer that is bound by trastuzumab when an antibody that stimulates CD137 is added. Finally, we will demonstrate that this combination of two antibodies, trastuzumab, which targets the HER2+ breast cancer, and the CD137 antibody, which stimulates the NK cell, cures human breast cancer in a mouse model.

This approach to breast cancer challenges the current practice. No NK cell stimulating antibodies are part of standard practice for any cancer type. At present, there is a unique opportunity to move this concept rapidly forward to the clinic and patients with breast cancer. A stimulating CD137 antibody is currently in Phase I and Phase II trials for patients with solid tumors. The available safety and dosing data from these trials will allow rapid initiation of a combination trial with trastuzumab. If the preclinical foundation of research we propose is successful, a Phase I/II clinical trial of trastuzumab and CD137 antibody would be possible within 18-36 months.

In 2010 a projected 40,000 women will die from breast cancer, despite best current therapies including the monoclonal antibody against HER2, trastuzumab. We believe that we can now take monoclonal antibody therapy of cancer to a new level of efficacy by increasing the ability of NK cells to kill tumor with a stimulating CD137 antibody. Therapies that increase NK cell function uniquely offer the ability to improve trastuzumab without increasing toxicity to normal tissue. I have made the identification of such novel and innovative therapies that stimulate the immune response against breast cancer my career goal. CD137 represents a proof of concept that targeting the immune response, metaphorically pushing on the immune gas pedal, can provide significant antitumor activity without risk of systemic toxicity or tumor resistance as we observe with standard chemotherapies. With a graduate degree in clinical trial design, my career goals also include the design and oversight of early phase clinical trials. Ultimately, this therapy, CD137 antibody, and future immune-stimulating antibodies will affect all patients with HER2+ breast cancer with the goal of curing patients with newly diagnosed disease and prolonging life with a preserved quality of life for patients with advanced HER2+ breast cancer.