HER2 Support Group Forums - View Single Post - GM-CSF as therapy

Rich66 · 11-12-2009, 09:48 PM

Our Experts

Leisha Emens, M.D., Ph.D.

Phone: (410) 955-8964

Fax: (410) 614-8216

Titles
Associate Professor of Oncology
Schools/Degrees
M.D., Medicine, Baylor College of Medicine, Houston, TX
Ph.D., Cell Biology, Baylor College of Medicine, Houston, TX
Training
Clinical Fellow in Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD

Senior Clinical and Research Fellow in Medical Oncology, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD

Susan B. Komen Clinical Breast Cancer Fellowship, Johns Hopkins Oncology Center

Intern and Resident, Internal Medicine, University of Texas Southwestern Affiliated Hospitals, Parkland Memorial Hospital and Dallas VA Medical Center, Dallas, TX

Postdoctoral Research Fellow, Laboratory of Biological Chemistry, National Cancer Instutitute, National Institutes of Health, Bethesda, MD

Predoctoral Fellow, Baylor College of Medicine, Houston, TX
Certifications
Internal Medicine
Medical Oncology
Hematology

Clinical Interests
Medical Oncology
Breast Cancer
Immunotherapy

PhysicianLeisha Emens and her patients are featured in the Baltimore Sun regarding a clinical trial on a breast cancer vaccine

Research Summary
Dr. Emens develops and 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 is testing 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 will yield insight into relevant immunoregulatory pathways in humans that will support the better design of future vaccine trials. Dr. Emens has also investigated the addition of monoclonal antibodies that target either the tumor itself (HER-2/neu), or the tumor microenvironment (vascular endothelial growth factor receptor 2 (VEGFR2) to chemotherapy-modulated vaccination. Both add futher to the antitumor effect of the vaccine. In particular, HER-2/neu-specific monoclonal antibodies augment antigen processing and presentation, resulted in higher numbers of CD8+ T cells after chemotherapy-modulated vaccination in the presence of the antibody. Based on these data, Dr. Emens is preparing to launch a clinical trial testing the HER-2/neu-specific monoclonal antibody in combination with CY-modulated vaccination in patients with HER-2/neu-overexpressing breast cancer. 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 to improve breast cancer therapy.

Journal Citations
Davis-Sproul, J. M., Harris, M. P., Davidson, N. E., Kobrin, B. J., Jaffee, E. M. & Emens, L. A. (2005). Cost-effective manufacture of an allogeneic GM-CSF-secreting breast tumor vaccine in an academic cGMP facility. Cytotherapy 7, 46-56.

Emens, L. (2008). Jump-Starting Tumor Immunity with Breast Cancer Therapeutics. In: Cancer Vaccines and Tumor Immunity, ed. J.W.H.B.D. Rimas Orentas: Johnson, John Wiley and Sons, Inc.

Emens, L. A. & Jaffee, E. M. (2005). Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res 65, 8059-64.

Emens, L. A. (2006). Editorial. Int Rev Immunol 25, 259-68.

Emens, L. A. (2006). Roadmap to a better therapeutic tumor vaccine. Int Rev Immunol 25, 415-43.

Emens, L. A. 2008. Chemotherapy and tumor immunity: an unexpected collaboration. Front Biosci 13:249-57.

Emens, L. A., Reilly, R. T. & Jaffee, E. M. (2005). Cancer vaccines in combination with multimodality therapy. Cancer Treat Res 123, 227-45.

Emens, L., Miller, KD, and Mehta, R. (2008). Physician Roles in Academia: The Physician–Scientist, Clinical Investigator, and Clinician-Educator. . In: Career Resources Guide for the American Society of Clinical Oncology., ed. L. Hutchins, Blayney, DW, Ochs, JS, and Schwartz, JE: ASCO, 150-164.

Emens, L.A. (2008). Cancer vaccines: on the threshold of success. Expert Opin Emerg Drugs 13, 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., and Jaffee, E.M. (2008). Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. J Clin Invest 118, 1700-1711.

Manning, E. A., J. G. Ullman, J. M. Leatherman, J. M. Asquith, T. R. Hansen, T. D. Armstrong, D. J. Hicklin, E. M. Jaffee, and L. A. Emens. 2007. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res 13:3951-9.

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. (2006). OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. J Immunol 176, 974-83.

Zellars, R.C., Stearns, V., Frassica, D., Asrari, F., Tsangaris, T., Myers, L., DiPasquale, S., Lange, J., Jacobs, L., Emens, L.A., Armstrong, D., Fetting, J., Garrett-Mayer, E., Davidson, N.E. and Wolff, A.C. (2009). Feasibility Trial of Partial Breast Irradiation with Concurrent Dose-Dense Doxorubicin and Cyclophosphamide in Early Stage Breast Cancer. J Clin Onc 27, 2816-2822.

Davis-Sproul, J., Harris, M. P., Davidson, N. E., Kobrin, B. J., Jaffee, E. M., & Emens, L. A. 2005. Cost-effective manufacture of an allogeneic GM-CSF-secreting breast tumor vaccine in an academic cGMP facility. Cytotherapy. 7:46-56.
Emens, L. A. 2005. Towards a breast cancer vaccine: the next steps. Expert Rev. Vaccines. 4:831-841.

Emens, L. A., & Jaffee, E. M. 2005. Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res. 65:8059-8064.

Ercolini, A. M., Ladle, B. H., Manning, E. A., Pfannenstiel, L. W., Armstrong, T. D., Machiels, J. P., et al. 2005. Recruitment of latent pools of high avidity CD8(+) T cells to the antitumor immune response. J. Exp. Med. 201:1591-1602.

Clin Cancer Res. 2009 Nov 15;15(22):7036-44. Epub 2009 Nov 10.
Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial.

Slingluff CL Jr, Petroni GR, Olson WC, Smolkin ME, Ross MI, Haas NB, Grosh WW, Boisvert ME, Kirkwood JM, Chianese-Bullock KA.
Department of Surgery/Division of Surgical Oncology, Department of Public Health Sciences, and Department of Medicine/Division of Hematology-Oncology, University of Virginia, Charlottesville, Virginia, USA.
PURPOSE: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites. EXPERIMENTAL DESIGN: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DR-restricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 microg GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN-gamma ELIspot assay and tetramer analysis. Clinical outcomes were recorded. RESULTS: CD8+ T-cell response rates to the 12 MHC class I-restricted melanoma peptides (by day 50) with or without GM-CSF were 34% and 73%, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95% versus 77%; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95% confidence interval) were 76% (67-83%) and 52% (43-61%), respectively, with too few events to assess differences by study group. CONCLUSIONS: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans.

PMID: 19903780 [PubMed - in process]

J Clin Oncol. 2009 Oct 5. [Epub ahead of print]
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.

Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, Davidson NE, Jaffee EM.
Sidney Kimmel Comprehensive Cancer Center, the Departments of Oncology, Pathology, and Pharmacology, and the Programs in Pathobiology, Immunology, and Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Tumor Vaccine Group, University of Washington, Seattle, WA; and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
PURPOSE: Granulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer. PATIENTS AND METHODS: We conducted a 3 x 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity. RESULTS: Twenty-eight patients received at least one immunization, and 16 patients received four immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received vaccine alone or with 200 mg/m(2) CY. HER2-specific antibody responses were enhanced by 200 mg/m(2) CY and 35 mg/m(2) DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m(2) and DOX at 35 mg/m(2) is the combination that produced the highest antibody responses. CONCLUSION: First, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m(2). Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted.

PMID: 19805669 [PubMed - as supplied by publisher]

http://www.wsoctv.com/health/19540065/detail.html

Treating Lung Metastases: Aerosolized Chemotherapy
When osteosarcoma metastasizes, 85 percent of the time it goes to the lungs. Chemotherapy may be given to control the growth and/or slow the spread of the cancer. But the treatment can have serious side effects, like hair loss, fatigue and an increased risk for infection. The side effects occur because the anti-cancer drugs have to travel through the body to get at the cancer site in the lungs, damaging healthy cells along the way.Researchers are now testing a new way to treat osteosarcoma lung metastases, by using inhaled chemotherapy. The treatment, delivered through an inhaler, uses GM-CSF (granulocyte macrophage colony stimulating factor), also known as LEUKINE® (sargramostim), to stimulate the production of white blood cells that fight the tumor. Pete Anderson, MD, PhD, Cancer Researcher with MD Anderson Cancer Center in Houston, says the drug is normally given as a shot under the skin. But as white blood cells numbers increase, patients can experience a significant amount of aches and bone pain. When the treatment is given in an inhaled form, the drug goes directly into the airways and only the lung cells are affected. Thus, patients don’t experience the painful side effects.The inhaled chemotherapy is combined with another treatment, an experimental drug called mifamurtide, or L-MTP-PE. This medication binds to white blood cells and boosts their activity. Although given intravenously, it readily travels to the lungs where it, hopefully, strengthens the ability of the white blood cells to fight the tumor. Anderson says MTP-PE can cause high fever and chills, so patients are usually pretreated with medications, like ibuprofen or acetaminophen, to prevent the side effects.

11-12-2009, 09:48 PM	#6
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: GM-CSF as therapy Our Experts Leisha Emens, M.D., Ph.D. Phone: (410) 955-8964 Fax: (410) 614-8216 Titles Associate Professor of Oncology Schools/Degrees M.D., Medicine, Baylor College of Medicine, Houston, TX Ph.D., Cell Biology, Baylor College of Medicine, Houston, TX Training Clinical Fellow in Hematology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD Senior Clinical and Research Fellow in Medical Oncology, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD Susan B. Komen Clinical Breast Cancer Fellowship, Johns Hopkins Oncology Center Intern and Resident, Internal Medicine, University of Texas Southwestern Affiliated Hospitals, Parkland Memorial Hospital and Dallas VA Medical Center, Dallas, TX Postdoctoral Research Fellow, Laboratory of Biological Chemistry, National Cancer Instutitute, National Institutes of Health, Bethesda, MD Predoctoral Fellow, Baylor College of Medicine, Houston, TX Certifications Internal Medicine Medical Oncology Hematology Clinical Interests Medical Oncology Breast Cancer Immunotherapy PhysicianLeisha Emens and her patients are featured in the Baltimore Sun regarding a clinical trial on a breast cancer vaccine Research Summary Dr. Emens develops and 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 is testing 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 will yield insight into relevant immunoregulatory pathways in humans that will support the better design of future vaccine trials. Dr. Emens has also investigated the addition of monoclonal antibodies that target either the tumor itself (HER-2/neu), or the tumor microenvironment (vascular endothelial growth factor receptor 2 (VEGFR2) to chemotherapy-modulated vaccination. Both add futher to the antitumor effect of the vaccine. In particular, HER-2/neu-specific monoclonal antibodies augment antigen processing and presentation, resulted in higher numbers of CD8+ T cells after chemotherapy-modulated vaccination in the presence of the antibody. Based on these data, Dr. Emens is preparing to launch a clinical trial testing the HER-2/neu-specific monoclonal antibody in combination with CY-modulated vaccination in patients with HER-2/neu-overexpressing breast cancer. 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 to improve breast cancer therapy. Journal Citations Davis-Sproul, J. M., Harris, M. P., Davidson, N. E., Kobrin, B. J., Jaffee, E. M. & Emens, L. A. (2005). Cost-effective manufacture of an allogeneic GM-CSF-secreting breast tumor vaccine in an academic cGMP facility. Cytotherapy 7, 46-56. Emens, L. (2008). Jump-Starting Tumor Immunity with Breast Cancer Therapeutics. In: Cancer Vaccines and Tumor Immunity, ed. J.W.H.B.D. Rimas Orentas: Johnson, John Wiley and Sons, Inc. Emens, L. A. & Jaffee, E. M. (2005). Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res 65, 8059-64. Emens, L. A. (2006). Editorial. Int Rev Immunol 25, 259-68. Emens, L. A. (2006). Roadmap to a better therapeutic tumor vaccine. Int Rev Immunol 25, 415-43. Emens, L. A. 2008. Chemotherapy and tumor immunity: an unexpected collaboration. Front Biosci 13:249-57. Emens, L. A., Reilly, R. T. & Jaffee, E. M. (2005). Cancer vaccines in combination with multimodality therapy. Cancer Treat Res 123, 227-45. Emens, L., Miller, KD, and Mehta, R. (2008). Physician Roles in Academia: The Physician–Scientist, Clinical Investigator, and Clinician-Educator. . In: Career Resources Guide for the American Society of Clinical Oncology., ed. L. Hutchins, Blayney, DW, Ochs, JS, and Schwartz, JE: ASCO, 150-164. Emens, L.A. (2008). Cancer vaccines: on the threshold of success. Expert Opin Emerg Drugs 13, 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., and Jaffee, E.M. (2008). Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. J Clin Invest 118, 1700-1711. Manning, E. A., J. G. Ullman, J. M. Leatherman, J. M. Asquith, T. R. Hansen, T. D. Armstrong, D. J. Hicklin, E. M. Jaffee, and L. A. Emens. 2007. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res 13:3951-9. 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. (2006). OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. J Immunol 176, 974-83. Zellars, R.C., Stearns, V., Frassica, D., Asrari, F., Tsangaris, T., Myers, L., DiPasquale, S., Lange, J., Jacobs, L., Emens, L.A., Armstrong, D., Fetting, J., Garrett-Mayer, E., Davidson, N.E. and Wolff, A.C. (2009). Feasibility Trial of Partial Breast Irradiation with Concurrent Dose-Dense Doxorubicin and Cyclophosphamide in Early Stage Breast Cancer. J Clin Onc 27, 2816-2822. Davis-Sproul, J., Harris, M. P., Davidson, N. E., Kobrin, B. J., Jaffee, E. M., & Emens, L. A. 2005. Cost-effective manufacture of an allogeneic GM-CSF-secreting breast tumor vaccine in an academic cGMP facility. Cytotherapy. 7:46-56. Emens, L. A. 2005. Towards a breast cancer vaccine: the next steps. Expert Rev. Vaccines. 4:831-841. Emens, L. A., & Jaffee, E. M. 2005. Leveraging the activity of tumor vaccines with cytotoxic chemotherapy. Cancer Res. 65:8059-8064. Ercolini, A. M., Ladle, B. H., Manning, E. A., Pfannenstiel, L. W., Armstrong, T. D., Machiels, J. P., et al. 2005. Recruitment of latent pools of high avidity CD8(+) T cells to the antitumor immune response. J. Exp. Med. 201:1591-1602. Clin Cancer Res. 2009 Nov 15;15(22):7036-44. Epub 2009 Nov 10. Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial. Slingluff CL Jr, Petroni GR, Olson WC, Smolkin ME, Ross MI, Haas NB, Grosh WW, Boisvert ME, Kirkwood JM, Chianese-Bullock KA. Department of Surgery/Division of Surgical Oncology, Department of Public Health Sciences, and Department of Medicine/Division of Hematology-Oncology, University of Virginia, Charlottesville, Virginia, USA. PURPOSE: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites. EXPERIMENTAL DESIGN: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DR-restricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 microg GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN-gamma ELIspot assay and tetramer analysis. Clinical outcomes were recorded. RESULTS: CD8+ T-cell response rates to the 12 MHC class I-restricted melanoma peptides (by day 50) with or without GM-CSF were 34% and 73%, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95% versus 77%; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95% confidence interval) were 76% (67-83%) and 52% (43-61%), respectively, with too few events to assess differences by study group. CONCLUSIONS: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans. PMID: 19903780 [PubMed - in process] J Clin Oncol. 2009 Oct 5. [Epub ahead of print] 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. Emens LA, Asquith JM, Leatherman JM, Kobrin BJ, Petrik S, Laiko M, Levi J, Daphtary MM, Biedrzycki B, Wolff AC, Stearns V, Disis ML, Ye X, Piantadosi S, Fetting JH, Davidson NE, Jaffee EM. Sidney Kimmel Comprehensive Cancer Center, the Departments of Oncology, Pathology, and Pharmacology, and the Programs in Pathobiology, Immunology, and Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Tumor Vaccine Group, University of Washington, Seattle, WA; and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA. PURPOSE: Granulocyte-macrophage colony-stimulating factor (GM-CSF) -secreting tumor vaccines have demonstrated bioactivity but may be limited by disease burdens and immune tolerance. We tested the hypothesis that cyclophosphamide (CY) and doxorubicin (DOX) can enhance vaccine-induced immunity in patients with breast cancer. PATIENTS AND METHODS: We conducted a 3 x 3 factorial (response surface) dose-ranging study of CY, DOX, and an HER2-positive, allogeneic, GM-CSF-secreting tumor vaccine in 28 patients with metastatic breast cancer. Patients received three monthly immunizations, with a boost 6 to 8 months from study entry. Primary objectives included safety and determination of the chemotherapy doses that maximize HER2-specific immunity. RESULTS: Twenty-eight patients received at least one immunization, and 16 patients received four immunizations. No dose-limiting toxicities were observed. HER2-specific delayed-type hypersensitivity developed in most patients who received vaccine alone or with 200 mg/m(2) CY. HER2-specific antibody responses were enhanced by 200 mg/m(2) CY and 35 mg/m(2) DOX, but higher CY doses suppressed immunity. Analyses revealed that CY at 200 mg/m(2) and DOX at 35 mg/m(2) is the combination that produced the highest antibody responses. CONCLUSION: First, immunotherapy with an allogeneic, HER2-positive, GM-CSF-secreting breast tumor vaccine alone or with CY and DOX is safe and induces HER2-specific immunity in patients with metastatic breast cancer. Second, the immunomodulatory activity of low-dose CY has a narrow therapeutic window, with an optimal dose not exceeding 200 mg/m(2). Third, factorial designs provide an opportunity to identify the most active combination of interacting drugs in patients. Further investigation of the impact of chemotherapy on vaccine-induced immunity is warranted. PMID: 19805669 [PubMed - as supplied by publisher] http://www.wsoctv.com/health/19540065/detail.html Treating Lung Metastases: Aerosolized Chemotherapy When osteosarcoma metastasizes, 85 percent of the time it goes to the lungs. Chemotherapy may be given to control the growth and/or slow the spread of the cancer. But the treatment can have serious side effects, like hair loss, fatigue and an increased risk for infection. The side effects occur because the anti-cancer drugs have to travel through the body to get at the cancer site in the lungs, damaging healthy cells along the way.Researchers are now testing a new way to treat osteosarcoma lung metastases, by using inhaled chemotherapy. The treatment, delivered through an inhaler, uses GM-CSF (granulocyte macrophage colony stimulating factor), also known as LEUKINE® (sargramostim), to stimulate the production of white blood cells that fight the tumor. Pete Anderson, MD, PhD, Cancer Researcher with MD Anderson Cancer Center in Houston, says the drug is normally given as a shot under the skin. But as white blood cells numbers increase, patients can experience a significant amount of aches and bone pain. When the treatment is given in an inhaled form, the drug goes directly into the airways and only the lung cells are affected. Thus, patients don’t experience the painful side effects.The inhaled chemotherapy is combined with another treatment, an experimental drug called mifamurtide, or L-MTP-PE. This medication binds to white blood cells and boosts their activity. Although given intravenously, it readily travels to the lungs where it, hopefully, strengthens the ability of the white blood cells to fight the tumor. Anderson says MTP-PE can cause high fever and chills, so patients are usually pretreated with medications, like ibuprofen or acetaminophen, to prevent the side effects. __________________ Mom's treatment history (link)