Clinical Trial Keywords:
Breast cancer, Vaccine
Dr. Emens tests active vaccination strategies for breast cancer treatment that are optimally integrated with traditional anticancer therapies and newer biologically targeted therapies in additive or synergistic ways. She developed a genetically-modified, cell-based vaccine for breast cancer that secretes the immune-stimulating hormone granulocyte-macrophage colony-stimulating factor (GM-CSF) and expresses HER-2. She first tested the vaccine in combination with low doses of Cyclophosphamide (CY) and Doxorubicin (DOX) in patients with Stage 4 breast cancer. In a mouse model of spontaneous breast cancer where the vaccine does not work, adding CY and DOX cures about 30% of tumor-bearing mice. This chemotherapy effect is largely due to the ability of CY to turn off a special type of immune cell (regulatory T cell) that keeps immune responses shut down. Analysis of patient samples on this trial demonstrated that the vaccine alone is active in inducing HER-2-specific T cell responses, but HER-2-specific antibody levels remain low. CY 200 mg/m2 and DOX 35 mg/m2 augmented HER-2-specific antibody responses compared to vaccine alone, but doses of CY higher than 200 mg/m2 inhibited the vaccine. Dr. Emens and her team are now actively analyzing the sera of HER-2 responders to identify novel targets of the vaccine-induced immune response for further study. She has also investigated the addition of monoclonal antibodies that target either the tumor itself (HER-2), or the tumor microenvironment (vascular endothelial growth factor receptor 2 (VEGFR2) to chemotherapy-modulated vaccination. Both add further to the antitumor effect of the vaccine. In particular, HER-2-specific monoclonal antibodies augment antigen processing and presentation, results in higher numbers of CD8+ T cells after chemotherapy-modulated vaccination in the presence of the antibody. Accordingly, Dr. Emens has launched three clinical trials testing the HER-2-specific monoclonal antibody Trastuzumab in combination with CY-modulated vaccination, two in patients with HER-2-overexpressing breast cancer, and one in patients with breast cancer that does not over-express HER-2. Finally, Dr. Emens is exploring modulating distinct aspects of the tumor microenvironment with novel tyrosine kinase inhibitors and novel molecular therapeutics. The overall goal of Dr. Emens research is to elucidate mechanisms of immunoregulation in patients with breast cancer using the vaccine in combination with standard breast cancer drugs and novel therapeutics. These studies should identify novel drug targets and new therapies to improve breast cancer outcomes.
Emens, L.A. Roadmap to a better therapeutic tumor vaccine. International reviews of immunology. 2006 Sep-Dec;25(5):415-443.
Emens, L.A. Cancer vaccines: toward the next revolution in cancer therapy. International reviews of immunology. 2006 Sep-Dec;25(5):259-268.
Murata, S.; Ladle, B.H.; Kim, P.S.; Lutz, E.R.; Wolpoe, M.E.; Ivie, S.E.; Smith, H.M.; Armstrong, T.D.; Emens, L.A.; Jaffee, E.M.; Reilly, R.T. OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. J Immunol. 2006 Jan 15;176(2):974-983.
Manning, E.A.; Ullman, J.G.; Leatherman, J.M.; Asquith, J.M.; Hansen, T.R.; Armstrong, T.D.; Hicklin, D.J.; Jaffee, E.M.; Emens, L.A. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res. 2007 Jul 1;13(13):3951-3959.
Emens, L.A. Chemotherapy and tumor immunity: an unexpected collaboration. Front Biosci. 2008 Jan. 1;13:249-257.
Emens, L.A. Jump-Starting Tumor Immunity with Breast Cancer Therapeutics. In: Rimas Orentas, J.W.H., Byron D. Johnson, editor, Cancer Vaccines and Tumor Immunity: Johnson, John Wiley and Sons, Inc; 2008.
Emens, L.A. Cancer vaccines: on the threshold of success. Expert opinion on emerging drugs. 2008 Jun;13(2):295-308.
Kim, P.S.; Armstrong, T.D.; Song, H.; Wolpoe, M.E.; Weiss, V.; Manning, E.A.; Huang, L.Q.; Murata, S.; Sgouros, G.; Emens, L.A.; Reilly, R.T.; Jaffee, E.M. Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. J Clin Invest. 2008 May;118(5):1700-1711.
Balmanoukian, A.; Zhang, Z.; Jeter, S.; Slater, S.; Armstrong, D.K.; Emens, L.A.; Fetting, J.H.; Wolff, A.C.; Davidson, N.E.; Jacobs, L.; Lange, J.; Tsangaris, T.N.; Zellars, R.; Gabrielson, E.; Stearns, V. African American women who receive primary anthracycline- and taxane-based chemotherapy for triple-negative breast cancer suffer worse outcomes compared with white women. J Clin Oncol. 2009 Aug 1;27(22):e35-37; author reply e38-39.
Emens, L.A. GM-CSF-secreting vaccines for solid tumors. Curr Opin Investig Drugs. 2009 Dec;10(12):1315-1324.
Emens, L.A.; Asquith, J.M.; Leatherman, J.M.; Kobrin, B.J.; Petrik, S.; Laiko, M.; Levi, J.; Daphtary, M.M.; Biedrzycki, B.; Wolff, A.C.; Stearns, V.; Disis, M.L.; Ye, X.; Piantadosi, S.; Fetting, J.H.; Davidson, N.E.; Jaffee, E.M. Timed sequential treatment with cyclophosphamide, doxorubicin, and an allogeneic granulocyte-macrophage colony-stimulating factor-secreting breast tumor vaccine: a chemotherapy dose-ranging factorial study of safety and immune activation. J Clin Oncol. 2009 Dec 10;27(35):5911-5918.
Emens, L.A.; Davidson, N.E. Postoperative endocrine therapy for invasive breast cancer. Cancer Treat Res. 2009;151:139-161.
Zellars, R.C.; Stearns, V.; Frassica, D.; Asrari, F.; Tsangaris, T.; Myers, L.; DiPasquale, S.; Lange, J.R.; Jacobs, L.K.; Emens, L.A.; Armstrong, D.K.; Fetting, J.H.; Garrett-Mayer, E.; Davidson, N.E.; Wolff, A.C. Feasibility trial of partial breast irradiation with concurrent dose-dense doxorubicin and cyclophosphamide in early-stage breast cancer. J Clin Oncol. 2009 Jun 10;27(17):2816-2822.
Chumsri, S.; Jeter, S.; Jacobs, L.K.; Nassar, H.; Armstrong, D.K.; Emens, L.A.; Fetting, J.H.; Lange, J.R.; Riley, C.; Tsangaris, T.N.; Wolff, A.C.; Zellars, R.; Zhang, Z.; Stearns, V. Pathologic complete response to preoperative sequential doxorubicin/cyclophosphamide and single-agent taxane with or without trastuzumab in stage II/III HER2-positive breast cancer. Clin Breast Cancer. 2010 Feb;10(1):40-45.
Descourt, P.; Carlier, T.; Du, Y.; Song, X.; Buvat, I.; Frey, E.C.; Bardies, M.; Tsui, B.M.; Visvikis, D. Implementation of angular response function modeling in SPECT simulations with GATE. Phys Med Biol. 2010 May 7;55(9):N253-266.
Edwards, J.P.; Emens, L.A. The multikinase inhibitor Sorafenib reverses the suppression of IL-12 and enhancement of IL-10 by PGE in murine macrophages. Int Immunopharmacol. 2010 Oct;10(10):1220-1228.
Emens, L.A. Chemoimmunotherapy. Cancer J. 2010 Jul-Aug;16(4):295-303.
Gupta, R.; Emens, L.A. GM-CSF-secreting vaccines for solid tumors: moving forward. Discov Med. 2010 Jul;10(50):52-60.
Pfannenstiel, L.W.; Lam, S.S.; Emens, L.A.; Jaffee, E.M.; Armstrong, T.D. Paclitaxel enhances early dendritic cell maturation and function through TLR4 signaling in mice. Cell Immunol. 2010;263(1):79-87.
Towler, W.I.; James, M.M.; Ray, S.C.; Wang, L.; Donnell, D.; Mwatha, A.; Guay, L.; Nakabiito, C.; Musoke, P.; Jackson, J.B.; Eshleman, S.H. Analysis of HIV diversity using a high-resolution melting assay. AIDS Res Hum Retroviruses. 2010 Aug;26(8):913-918.