John M. Kirkwood, M.D.
Department of Medicine
Co-leader - UPCI Melanoma Program
University of Pittsburgh
HCC Suite 1.32
5117 Centre Avenue
Pittsburgh, PA 15213-1863
Our clinical and laboratory program has primary goals to develop improved therapy for inoperable advanced melanoma that will prolong the survival and/or progression-free interval of patients with stage III-IV melanoma. Given this aim, we have previously performed studies focusing upon chemotherapy and biological agents that represent the intermediates of the host immune system, including T cells, dendritic cells, antibodies, cytokines, and interferons, and combinations of these agents. Our early studies of the interferons led us to the importance of the STAT family of transcription factors, one of which, STAT3, is expressed at high levels in melanoma cells. We discovered that the interferons (interferon alfa-2) reverses this up-regulation, and re-arms the immune system in patients with melanoma. We have now undertaken studies to elucidate the role of interferon-alpha in relation to vaccination, and the ability of anti-melanoma antibodies to kill melanoma cells through a process known as antibody-dependent cellular cytotoxicity. We are also evaluating the effects of interferon alfa-2 in combination with new classes of antibodies with immunomodulatory properties (anti-CTLA4 blocking antibodies). Currently, we are conducting clinical trials in which vaccination is followed by interferon-alpha (UPCI 04-125, 03-118), or treatment with an antibody to melanoma ganglioside GD3 (KW2871) is administered in conjunction with interferon-alpha (UPCI 07-023). A third trial involves treatment with a blocking antibody (tremelimumab) to the cytotoxic T-lymphocyte antigen 4 (CTLA-4) concurrent with interferon-alpha (UPCI 05-125).
Our second major objective is to develop therapies that will prevent the relapse and mortality from melanoma, what are known as post-surgical adjuvant studies. Melanomas, or the factors like UV that cause melanoma, induce immune tolerance that is more profound in advanced disease than earlier in the spread of the malignancy. Given this, we have focused upon the development of therapies that can be given at the time of initial surgery (the adjuvant setting) in hopes that the abrogation of tolerance to tumor cell antigens would be more successful and increase overall and/or relapse-free survival of patients at earlier stages of operable melanoma. Our recent findings using high-dose interferon alfa-2b as tested in several cooperative group trials, suggest that this immunological intervention is significantly more effective in settings of minimal residual disease. We are now initiating an adjuvant analysis of the anti-CTLA4 blocking antibody, ipilimumab, to investigate the effects of this therapy at the level of the key host immune processing cell, the dendritic cell, and the T cell effector and regulatory cell networks. The ultimate goal of these studies is to identify tumor antigen-specific responses that underlie curative therapy. To dissect the complex response in early operable melanoma, we are pursuing high-throughput proteomic analysis of the correlates of therapy with interferon-alpha, evaluating dose and formulation of interferon-alpha in relation to the sentinel lymph node. We are also analyzing the immunological effects of ipilimumab administered as a neo-adjuvant therapy for patients with stage IIIB melanoma, and plan to compare ipilimumab and interferon-alpha effects as adjuvant therapies for stage IIIB and IV resectable melanoma.
Kirkwood JM, Tarhini AA, Panelli MC, Moschos SJ, Zarour HM, Butterfield LH, Gogas HJ (2008). Next generation of immunotherapy for melanoma. J Clin Oncol. 26: 3445-3455.
Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, Suman VJ, Moon J, Sondak VK, Atkins MB, Eisenhauer EA, Parulekar W, Markovic SN, Saxman S, Kirkwood JM (2008). Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials. J Clin Oncol. 26: 527-534.
Yurkovetsky ZR, Kirkwood JM, Edington HD, Marrangoni AM, Velikokhatnaya L, Winans MT, Gorelik E, Lokshin AE (2007). Multiplex analysis of serum cytokines in melanoma patients treated with interferon-alpha2b. Clin Cancer Res. 13: 2422-2428.
Moschos SJ, Edington HD, Land SR, Rao UN, Jukic D, Shipe-Spotloe J, Kirkwood JM (2006). Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 24: 3164-3170.
Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, Panagiotou P, Polyzos A, Papadopoulos O, Stratigos A, Markopoulos C, Bafaloukos D, Pectasides D, Fountzilas G, Kirkwood JM (2006). Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med. 354: 709-718.