Leisha Emens, M.D., Ph.D.
Assistant Professor of Oncology
Tumor Immunology Program
Breast Cancer Program
Department of Oncology
Room 4M90
Bunting-Blaustein Cancer Research Building
410-502-7051 (phone)
410-614-8216 (fax)
emensle@jhmi.edu

Research Focus

Dr. Emens is dedicated to understanding the regulatory pathways that control the interaction between developing breast cancers and the immune system in human breast cancer, and to using that information to develop innovative immune-based treatments for breast cancer treatment and prevention. It is now clear that integrating tumor vaccines with other cancer therapeutics in ways that strategically circumvent systemic and local mechanisms of immune tolerance will be critical for immunotherapy to have a meaningful impact on treatment outcomes, even in early stage breast cancer. The number of standard and molecularly targeted therapies in common use for breast cancer treatment today identify this disease as a highly informative model system for dissecting the way that tumor biology and the immune system influence each other, and how therapies can impact that relationship in a therapeutically meaningful way. Dr. Emens currently has three major projects that aim to integrate laboratory and clinical research in order to better understand the immune response to human breast cancer, and to develop therapeutic vaccination regimens with clinical efficacy:

• The evaluation of mechanisms of immune activation and tolerance in human breast cancer. Dr. Emens has developed a human allogeneic, GM-CSF-secreting, HER-2/neu-overexpressing breast tumor vaccine for use as a tool to dissect mechanisms of immune activation and tolerance in patients with early and metastatic breast cancer. She is currently conducting two clinical trials that test the breast tumor vaccine in combination with standard breast cancer treatments in a strategic fashion that undermines established immune tolerance, augments immune activation, or both. By evaluating vaccine-induced immune responses to a sentinel antigen delivered by the vaccine (HER-2/neu), these studies should directly delineate mechanisms of immunoregulation relevant to breast cancer biology. The first study is a Phase I clinical trial testing the vaccine in sequence with low dose Cyclophosphamide (CY) and Doxorubicin (DOX). This study is designed to evaluate the hypothesis that CY can abrogate the influence of suppressive regulatory T cells, allowing the vaccine to activate high avidity antigen-specific T cells potent enough to control disease. The second is a Phase I/II clinical study testing CY-modulated vaccination in the setting of standard weekly Trastuzumab (Herceptin) therapy for metastastic HER-2/neu-positive breast cancer. This trial is designed to evaluate the hypothesis that both mitigating the suppressive influence of regulatory T cells with CY and augmenting antigen processing and presentation with Trastuzumab can augment the vaccine-induced immune response to levels sufficient to confer a clinical benefit over Trastuzumab alone. The most promising combinations will be tested as consolidation therapy after adjuvant treatment for high-risk primary breast cancer.
• The identification of tumor antigens in human breast cancer. Dr. Emens is also analyzing the serum and lymphocytes taken from patients enrolled on the breast tumor vaccine studies, and use them to identify and characterize novel targets of the antibody and T cell response in vaccinated patients. The aim of these studies is to identify functional antigenic targets in immunized study patients, validate them as tumor antigens or frank tumor rejection targets in preclinical models, and develop the proteins as targets for immunological or biological therapies to be tested in second generation clinical trials.
• The development of treatment strategies that manipulate the tumor microenvironment to enhance the activity of immune effectors in metastatic disease. The tumor microenvironment is increasingly recognized as a dynamic player in tumor progression and metastasis, and negatively modulates the host antitumor immune response. In the neu transgenic mouse model of spontaneous breast cancer, she is developing vaccines that directly target the tumor vasculature, and combination vaccination strategies that target the transformed tumor cell while simultaneously grooming the tumor microenvironment to facilitate a productive antitumor immune response. Specific targets under investigation include VEGFR2, HEYL, and COX-2, among others. Based on this work, Dr. Emens will develop a clinical trial that incorporates distinct strategies for modulating systemic and local mechanisms of immune tolerance with vaccination in patients with metastatic breast cancer.

Selected Publications

• Machiels, J-P, Reilly, RT, Emens, LA, Ercolini, AM, Okoye, F, and Jaffee, EM. 2001. Cyclophosphamide, Doxorubicin, and Paclitaxel Enhance the Antigen-Specific Anti-Tumor Immune Response of GM-CSF-secreting Whole Cell Vaccines in Tolerized Mice, Cancer Research 61: 3689.
• Wolpoe, ME, Lutz, ER, Ercolini, AC, Murata, S, Ivie, S, Garrett, ES, Emens, LA, Jaffee, EM, and Reilly, RT. 2003. HER-2/neu-specific Monoclonal Antibodies Collaborate with HER-2/neu-targeted Granulocyte-Macrophage Colony-Stimulating Factor-Secreting Whole-Cell Vaccination to Augment CD8 + T Cell Effector Function and Tumor-Free Survival in HER-2/neu Transgenic Mice. Journal of Immunology, 171: 161-169.
• Davis-Sproul, J, Harris, MP, Davidson, NE, Kobrin BJ, Jaffee, EM, and Emens, LA . 2005. Cost-Effective Manufacture of an Allogeneic Granulocyte-Macrophage Colony-Stimulating Factor-secreting Breast Tumor Vaccine in an Academic cGMP Facility, Cytotherapy, 7: 46-56.
• Ercolini, AM, Ladle, BH, Manning EM, Pfannenstiel LW, Armstrong, TD, Machiels, JP, Bieler, JG, Emens, LA, Reilly, RT, and Jaffee, EM. 2005. Recruitment of Latent Pools of High Avidity CD8 + T Cells to the Antitumor Immune Response. Journal of Experimental Medicine, 201: 1591-1602.
• Murata, S, Ladle, BH, Kim, PS, Lutz, ER, Wolpoe, ME, Smith, HM, Armstrong, TA, Emens, LA, Jaffee, EM, and Reilly, RT. 2006. OX40 Costimulation Synergizes with GM-CSF Whole Cell Vaccination to Overcome Established Tolerance to an Endogenous Tumor Antigen. Journal of Immunology, 176: 974-983.
• Manning, EA, Ullman, JGM, Hansen, TR, Armstrong, TD, Jaffee, EM, and Emens, LA . 2006. Multi-targeted Therapy with a HER-2/neu-specific Vaccine and a VEGF-R2 Inhibitor Enhances Anti-Tumor Immunity Through an Immune-Based Mechanism. manuscript under review.