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Oncologue, Volume 5, #2

Tumor Vaccines for Melanoma:
Discoveries Lead to New Approaches

Craig L. Slingluff Jr., MD, FACS
Associate Professor of Surgery
Chief, Division of Surgical Oncology
Director, Human Immune Therapy Center

    There is a common belief that a healthy immune system has a role in controlling cancer, and it is true that experimental manipulations of immune function have shown dramatic effects on tumor growth in animal models.  Attempts to control cancer with immunotherapy have been made for more than a century.  Despite such attempts, however, immunotherapy has only recently begun to take its place among more standard approaches to cancer therapy.  In the past 10 to 20 years, there have been several important discoveries about cell-mediated immunity, and these discoveries have led the way for the development of promising new therapies aimed at the immune response to cancer.

Animal Models in Immunologic Therapy
    In classic experiments performed several decades ago, experimental tumors were injected into mice, then resected.  That transient exposure to tumor cells resulted in immunity to subsequent tumor exposure.  Tumor immunity could be transferred to other syngeneic mice by transferring the lymphocytes. This demonstrated that tumor immunity is a property of lymphocytes.  Also, work done in the early 1980s revealed that injection of tumor-reactive cytotoxic T-lymphocytes (CTL) into mice with micrometastatic experimental tumors could dramatically protect against the outgrowth of lethal macrometastases.
    Even more striking has been the work done in the past few years with tumor vaccines composed of dendritic cells pulsed with tumor antigens.  In these studies reported by scientists at the University of Pittsburgh and Duke University, it was possible to eradicate gross tumor deposits after injection of these potent antigen-presenting cells.  Thus, recent studies using new tumor vaccine methods appear to be capable of dramatic tumor destruction mediated by the immune system.

Tumor Vaccines for Melanoma
    Two studies published in the March 1998 issue of the journal Nature Medicine provide exciting new evidence that tumor vaccine therapy, based on the new science of tumor immunology, can result in clinical response rates of 30 percent to 40 percent in stage IV melanoma patients. This is comparable to the results with chemotherapy for melanoma, but what is striking is that a few of the patients treated with such vaccines have had durable responses to immunotherapy, remaining free of disease for more than 15 months in some cases.  These trials have generally been associated with very little morbidity, which makes them attractive alternatives to the more toxic therapy available with cytotoxic chemotherapy or interferon.

Tumor Antigens Defined at UVa
    The University of Virginia has been a major contributor to the identification of target antigens recognized by cytotoxic T-lymphocytes.  Since 1991, the collaborative efforts of three laboratories at UVa have resulted in the identification of four new peptide antigens recognized by human CTL.  Some or all of the peptide antigens are being used in new vaccine trials just opened at the UVa (see sidebar below).  They are also being used in trials at the National Cancer Institute, the University of Pittsburgh and at clinical centers in Europe and Australia.

Vaccine Trials Offered at UVa
    Many patients with high-risk melanoma want additional therapy but do not want the toxicity associated with standard treatment options.  Meanwhile, patients with advanced metastatic disease often have no attractive standard therapy options.  The melanoma team at the University of Virginia offers a series of novel treatment options designed to address that need while also possibly leading to new treatments for the future.  Most of the treatments offered here were developed at least in part by UVa physicians, but UVa also offers participation in an international trial sponsored by the John Wayne Cancer Institute.  That trial is designed to determine whether aggressive surgical resection of advanced metastases, coupled with immunotherapy, has a survival advantage.

Patient Referral
    Patients interested in any of these treatments can be screened for their candidacy by calling Johanna Loomba at our Clinical Research Coordinator's Office (434-243-5946; jloomba@virginia.edu).  Consultation with members of the melanoma team is available for patients seeking information about treatment options for advanced melanoma.  Members of the melanoma team can advise patients about therapeutic options available throughout the country and globally.

Dr. Craig Slingluff, 434-924-1730, e-mail: cls8h@virginia.edu
Dr. William Grosh, 434-924-1904, e-mail: wwg9u@virginia.edu