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Melanoma

Program Director:
Economou, James S. M.D.
Glaspy, John M.D.

Contact Phone Number
(310) 825-2644

Description of Clinical Program
· OVERVIEW

The UCLA Melanoma Program offers comprehensive diagnostic and treatment for all stages of this disease. The Program is an integrated multidisciplinary clinical and research effort that includes surgical, medical and radiation oncologists, dermatologists, plastic and reconstructive surgeons, and basic scientists. The UCLA Melanoma Program is supported by the National Cancer Institute, generous donors and is a component of Solid Tumor Therapeutic Program of the UCLA Jonsson Comprehensive Cancer Center.

· PARTICIPATING FACULTY

CODIRECTORS
James S. Economou, MD, PhD Surgical Oncology 310-825-2644 Fax: 310-825-7575 jeconomou@mednet.ucla.edu
John A. Glaspy, M.D., MDH. Medical Oncology 310-794-1274 Fax: 310-794-1460 jglaspy@mednet.ucla.edu

FACULTY
Lisa Butterfield, Ph.D.Research310-206-8509Fax 310-267-2679lbutterfield@mednet.ucla.edu
Alistair Cochran, M,D,Pathology310-825-2743Fax 310-267-2058acochran@mednet.ucla.edu
Frederick Eilber, M.D.Surgical Oncology310-825-7086Fax 310-825-7575feilber@mednet.ucla.edu
Jennifer Haley, M.D.Dermatology310-206-6373Fax 310-794-7005jhaley@mednet.ucla.edu
Guy Julliard, M.D.Radiation Oncology310-825-7145Fax 310-794-9795juillard@radonc.ucla.edu
Antoni Ribas, M.D.Medical Oncology310-206-8509Fax 310-267-2679aribas@mednet.ucla.edu
James Watson, M.D.Plastic Surgery310-206-7520Fax 310-794-7933jpwatson@mednet.ucla.edu
· MALIGNANT MELANOMA

Melanoma accounts for about 4% of skin cancers but causes 80% of skin cancer deaths. The American Cancer Society estimates that about 51,400 new melanomas were diagnosed in the United States during 2001. The number of new melanomas is increasing; the incidence per 100,000 people each year has dramatically increased from 5.7 to 14.3. About 7,800 people in the United States are expected to die from melanoma during 2001 and this represents a 44% increase in the last 25 years.

Melanoma skin cancers arise from pigmented cells in the skin called melanocytes. These cells are found in the epidermis, the upper layer of the skin, and produce a pigment called melanin. Melanin pigment provides skin coloration and helps to protect deeper layers of the skin from solar radiation. Most malignant melanomas continue to produce melanin and thus these tumors are often brown or black. Some melanomas, however, do not contain this pigment and do not have this characteristic dark appearance. Melanomas most often arise in fair-skinned individuals, commonly on the lower legs of women and on the trunks of men. However, melanomas can arise anywhere on the body.

A number of risk factors have been identified for the development of melanoma skin cancers – excessive exposure to ultraviolet radiation from the sun, a fair complexion, an excessive number of moles and a family history of this disease. Attention to sun exposure and a careful total body skin surveillance are the keys to prevention and early diagnosis of this skin cancer.

· DIAGNOSIS

The UCLA PIGMENTED LESION CLINIC, based in the Department of Dermatology, provides comprehensive dermatologic diagnostic service for cutaneous lesions. Most primary melanomas should be identifiable on inspection with the classic clinical signs of alteration in color, size, texture, border irregularity, ulceration and bleeding. Color variations of pink, red, white and blue can frequently been seen in early lesions. A biopsy of a suspicious mole is the first consideration and, if possible, this should be excisional with a small amount of subcutaneous tissue. However, larger lesions can be sampled with a punch biopsy. Appointments for this clinic can be made by calling (310) 206-6371.

· SURGICAL ONCOLOGY TREATMENT

Melanomas generally require an additional surgical margin to be achieved around the primary site. This radial margin can vary from 0.5 to 2.0 cm depending upon the invasion of the primary melanoma. In addition, lymphatic mapping and sentinel lymph node biopsy is offered to patients to determine whether the melanoma has spread to regional lymph nodes. This technique was initially developed at UCLA and is now employed internationally as a minimally invasive but highly accurate staging technique. On the morning of surgery, patients have an injection of a small amount of radioactive tracer at the biopsy site which drains to lymphatics to the first lymph node, or sentinel node, in the lymph node basin. This sentinel node is the most likely place to find micrometastatic cells if the melanoma has spread. In the operating room, this lymph node can be identified with a hand-held gamma detector and biopsied through a small incision. In addition, a blue lymphatic dye is frequently used in the operating room as a visual aid to identification. Sentinel nodes can be identified and biopsied in 99% of patients and provide important staging information about the biological aggressiveness of the patient’s melanoma.

Comprehensive surgical care of melanoma patients is offered by the UCLA DIVISION OF SURGICAL ONCOLOGY. Appointments in the UCLA Melanoma Clinic – Surgical Oncology can be made by calling Dr. James Economou (310-825-2644) or Dr. Frederick Eilber (310-825-7086)

· MEDICAL ONCOLOGY

The UCLA Melanoma Program medical oncology team has a strong emphasis on experimental clinical trials arising from laboratory research, with the goal to improve on current medical management of patients with melanoma. The medical oncology team includes two physicians, Dr. John A. Glaspy, M.D., M.P.H., Professor of Medicine, and Dr. Antoni Ribas, M.D., Assistant Professor of Medicine. It also includes a nurse practitioner (Denise Oseguera, R.N.), a study coordinator (Huong T. Vu) and a data manager (Elisabeth Seja). This allows providing a comprehensive care for our patients, from adjuvant treatment of completely resected melanoma to decrease the likelihood that the cancer comes back, to treating metastatic melanoma that can no longer be taken out surgically.

Appointments in the UCLA Melanoma Clinic – Medical Oncology can be made by calling Dr. John A. Glaspy or Dr. Antoni Ribas at 310-794-4955. The office is located at the 100 UCLA Medical Plaza, Suite 550.

· ACTIVE AND PENDING CLINICAL TRIALS

IRB # 95-08-375: A Phase I/II Trial Testing MART-1 Peptide Immunization in Malignant Melanoma.

This trial uses dendritic cells generated in the laboratory from the patient's own blood loaded with the immune stimulating portion of the MART-1 melanoma antigen protein. Patients eligible for this protocol have to have a certain blood type, HLA-A2.1, and have a diagnosis of metastatic (stage IV) malignant melanoma expressing the MART-1 protein. The dendritic cells loaded with MART-1 are administered under the skin for a total of three vaccinations, one every two weeks. At regular intervals we obtain blood from the vaccinated patients and determine if their immune system has responded to the vaccinations, by detecting the ability of their lymphocytes to recognize and kill cancer cells expressing the MART-1 protein.

97-07-074: A Phase I/II Trial Testing MART-1 Genetic Immunization in Malignant Melanoma.

Based on the experience of our MART-1-peptide pulsed dendritic cell trial (IRB # 95-08-375) and our laboratory research, we are now ready to start a successor trial where the dendritic cells are modified genetically, using gene therapy techniques, to express the MART-1 tumor antigen. We have tested extensively these gene modified dendritic cell vaccines in animal models and using human cells in test tubes, trying to understand how they function before we use them in human subjects. Our results show that they activate more killer lymphocytes than other vaccination strategies tested in mice and with human cells in test tubes. Therefore, this trial arises from original innovative research pioneered by the UCLA Melanoma Program group.

UCLA IRB# 01-09-054 (Pfizer A3671001): A Phase I, Open Label, Non-Randomized Dose Escalation Study To Evaluate The Safety, Tolerability, Pharmacokinetics And Immune Function Effects Of CP-675,206 In Subjects With Solid Tumor Malignancies.

The goal of this experimental clinical trial is to determine the safety, tolerability, distribution and ability to stimulate the immune system by CP-675,206 in a phase 1 clinical trial. CP-675,206 is an antibody that targets and blocks the CTLA-4 receptor protein in the lymphocytes. Antibodies are normal human proteins that help fight infections by specifically binding to a protein. The CTLA-4 receptor is an “off switch” for the immune response that is present on the surface of lymphocytes. CP-675,206 has the ability to circulate through the blood and then bind to CTLA-4 on lymphocytes blocking the CTLA-4 “off switch” that limits the ability of lymphocytes to recognize and kill cancer cells. Studies in mice and primates suggest that this mode of treatment may be able to enhance the immune response to cancer cells. This trial will enroll subjects with stage III and IV melanoma at different dose levels.

Maxim MP-8899-104: A Phase III, Multi-center Controlled Trial with Stratified Randomization Comparing the Efficacy of Interleukin-2 (IL-2) plus Histamine Dihydrochloride (HDC) versus IL-2 Alone to Increase the Duration of Survival in Patients with AJCC Stage IV Maglignant Melanoma with Hepatic Metastasis.

Clinical evidence of the combined IL-2 plus Histamine therapy has been seen in patients with liver metastases from a prior study, MP-US-M01, a Maxim-sponsored Phase 3 study of IL-2 plus Histamine versus IL-2 alone in the treatment of advanced melanoma. Among patients with liver metastases, survival duration was improved in the IL-2 plus HDC compared to the group receiving only IL-2. The new study intends to validate that data, where patients will be allocated at random to two treatment arms, receive a low toxic IL-2 dose with or without the addition of the experimental drug, Histamine. IL-2 will be self-administered (after training) at a relatively low dose by a needle under the skin (subcutaneously) twice a day on the first 2 days of weeks 1 and 3 of each cycle. Histamine is given twice a day the first 5 days of weeks 1, 2, 3 and 4 per cycle. Patients will be educated to self-administer the study drugs at home. Eligible patients for this trial will be required to have stage IV melanoma with metastasis to the liver.

· RESEARCH PROGRAM


The laboratory of James S. Economou, M.D., Ph.D. is investigating how to stimulate the immune system to attack the cancer by using dendritic cells and genetic immunotherapy (the use of genetic material as vaccines).

The majority of cancers develop in human subjects despite a normal immune system. A special type of white blood cell, called the dendritic cell, is the key regulator of what and when the immune system reacts. Therefore, dendritic cells are like generals for the immune system, telling the fighter cells (the lymphocytes) when, how and against what they should attack (figure 1). We have learned how to grow these cells in the laboratory and how to load them with signals to direct the immune response against the cancer. Cancer cells have short proteins on their surface (called tumor antigens) that are recognized by the immune system. When the dendritic cells present the tumor antigens, the immune system is then signaled to attack the tumor cells.

With this understanding of the activation of the immune system, we have developed a procedure to insert the genes of antigens derived from cancer cells into dendritic cells. This involves the use of modified adenoviruses that carry the cancer cell antigen. These dendritic cells modified genetically to express cancer antigens have been extensively tested for their ability to protect mice from cancer cells (figure 2). Our results provide evidence of a potent stimulation of the immune system capable of rejecting a challenge of cancer cells expressing the same antigen. This vaccination technique, pioneered by our group, has been validated by multiple other investigators. We have studied the mechanism of this immune response and have elucidated which regulatory pathways are used by the immune system to limit this response. Furthermore, we have demonstrated that the same strategy of gene modified dendritic cell stimulation can generate killer lymphocytes using human blood cells in a test tube. Based on these data, we are in the final stages of gaining approval to test this novel form of treatment in human subjects with stage IV malignant melanoma.

Figure 1: Dendritic cells are ideally prepared to activate lymphocytes by presenting a tumor antigen on their surface. When this is recognized by the lymphocytes, they start dividing to generate more activated lymphocytes that recognize the tumor antigen and help fight the cancer cells.




Figure 2: Mouse dendritic cells are generated from the bone marrow. The dendritic cells are gene modified with the MART-1-expressing gene therapy vector AdVMART1, and injected back to mice. Then these mice are challenged with a large dose of melanoma cells. Mice that received the dendritic cell vaccine develop smaller tumors or do not develop tumor at all, while the mice that are not vaccinated all develop large tumors that grow rapidly.


In order to develop broadly applicable means of immunization for melanoma maintaining the same high level of immune activation, we are exploring the utility of a sequential immunization with a naked DNA plasmid and an adenoviral vector expressing the same melanoma antigen. This mode of immunization has the advantage of being stable in a vial since it does not require cell culture techniques to generate personalized vaccines.

In summary, the research program at the UCLA Melanoma Group is focused on the generation of hypothesis-driven translational research, testing innovative ideas in preclinical models and translating the most promising treatments to pilot clinical trials for patients with melanoma.

· RECENT PUBLICATIONS

Arthur, J. F., Butterfield, L. H., Kiertscher, S. M., Roth, M. D., Bui, L. A., Lau, R., Dubinett, S. M., Glaspy, J. and Economou, J. S. A comparison of Gene Transfer Methods in Human Dendritic Cells. Cancer Gene Therapy 4: 17-25, 1997.

Butterfield, L.H., Stoll, T. C., Lau, R. and Economou, J.S. Cloning and Analysis of MART-1/Melan-A human melanoma antigen promoter regions. Gene 191: 129-134, 1997.

Ribas, A., Butterfield, L.H., McBride, W.H., Jilani, S., Bui, L.A., Vollmer, C.M., Lau, R., Dissette, V.B., Hu, W., Chen, A., Glaspy, J. and Economou, J.S. Genetic Immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine dendritic cells. Cancer Research 57, 2865-2869, 1997

Butterfield, L.H., Ribas, A. and Economou, J.S. “DNA and Dendritic Cell-based Genetic Immunization against Cancer” in Gene Therapy of Cancer, Editors. Lattime, E., and Gerson, S. Academic Press, p 285-299, 1998.

Butterfield, L.H., Jilani, S., Chakraborty, N.G., Bui, L.A., Ribas, A., Dissette, V., Lau, R., Gamradt, S., Glaspy, J.A., McBride, W.H., Mukherji, B. and Economou, J.S. Generation of melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-1 adenovirus. Journal of Immunology, 161, 5607-5613, 1998.

Perez-Diez, A., Butterfield, L.H., Li, L., Chakraborty, N.G., Economou, J.S. and Mukherji, B. Generation of CD8+ and CD4+ T cell response to dendritic cells genetically engineered to express the MART-1/Melan-A gene. Cancer Research, 58, 5305-5309, 1998.

Lisa H. Butterfield, Antoni Ribas, James S. Economou. Genetic immunization for cancer. In Gene Therapy of Cancer, Edmund C. Lattime and Stanton L. Gerson Editors, Academic Press 1998, pp 285-300.

Ribas, A. Butterfield, L.H., McBride, W.H., Dissette, V.B., Koh, A., Vollmer, C.M., Hu, B., Chen, A., Eilber, F.C., Andrews, K.J., Glaspy, J.A. and Economou, J.S. Characterization of antitumor immunization to a defined melanoma antigen using genetically engineered murine dendritic cells. Cancer Gene Therapy, 6, 523-536, 1999.

Ribas, A., Bui, L.A., Butterfield, L.H., Vollmer, C.M., Jilani, S., Dissette, V.B., Glaspy, J.A., McBride, W.H., and Economou, J.S. Antitumor protection using murine Dendritic Cells pulsed with acid-eluted peptides from in vivo grown tumors of different immunogenicities. Anticancer Research, 19, 1165-1170, 1999.

Antoni Ribas, James S. Economou. Gene Therapy for Cancer. In Charles M. Haskell (editor): Cancer Treatment, Fifth Edition, W. B. Saunders 2000, pp 467-475.

Alistair Cochran, John A. Glaspy, Antoni Ribas, James S. Economou. Malignat Melanoma of the Skin. In Charles M. Haskell (editor): Cancer Treatment, Fifth Edition, W. B. Saunders 2000, pp 1158-1177.

Alistair Cochran, Sunita Bhuta, Eberhard Paul, Antoni Ribas. The Shifting Patterns of Metastatic Melanoma. Clinics in Laboratory Medicine, 2000 20: 759-83.

Antoni Ribas, Lisa H. Butterfield, James S. Economou. Genetic immunotherapy for cancer. The Oncologist, 2000; 5(2): 87-98.

Ribas, A., Butterfield, L.H., Hu, B., Dissette, V.B., Chen, A.Y., Koh, A., Glaspy, J.G., McBride, W.H. and Economou, J.S. Generation of T cell immunity to a murine melanoma using MART-1 engineered dendritic cells. Journal of Immunotherapy, 23, 59-66, 2000.

Miller, P.W., Sharma, S. Stolina, M. Butterfield, L.H., Luo, J., Lin Y., Dohadwala, M., Batra, R., Wu, L., Economou, J.S. and Dubinett, S.M. Intratumoral administration of adenoviral interleukin-7 gene-modified dendritic cells augments specific antitumor immunity and achieves tumor eradication. Human Gene Therapy 11, 53-65, 2000.

Ribas, A., Butterfield, L.H., Hu, B., Dissette, V.B., Koh, A., Lee, M.C., Andrews, K.J., Meng, W., Glaspy, J.G., McBride, W.H. and Economou, J.S. Immunological Effects of Repeated vaccinations with Adenovirally transduced dendritic cells expressing a melanoma antigen. Cancer Research, 60, 2218-2224, 2000.

Frost, P., Butterfield, L.H., Dissette, V.B., Economou, J.S. and Bonavida, B. Immunosensitization of melanoma tumor cells to non-MHC Fas-mediated killing by MART-127-35 specific CTL cultures. Journal of Immunology, 166, 3564-3573, 2001.

Antoni Ribas, Lisa H. Butterfield, James S. Economou. Cancer Immunotherapy using Gene-Modified Dendritic Cells. Current Gene Therapy 2001 (in press).

Ribas, A. Butterfield, L.H., Amarnani, S., Kim, D., Dissette, V.B., Meng, W.S., Miranda, G.A., Wang, H.-J., McBride, W.H., Glaspy, J.A., and J.S. Economou. CD40 Crosslinking Bypasses the Absolute Requirement for CD4 Cells after Immunization with Gene-Modified Dendritic Cells. Cancer Research, 2001 (in press).

· SUPPORT

RO1 CA 79976: “Dendritic cell-based Genetic Immunotherapy for Melanoma”.
P.I. James S. Economou, M.D., Ph.D.
Award time: 1/01/99-12/31/03.
NIH/NCI funding $861,660 total award.

T32 CA 75956: “UCLA Gene Medicine Training Program”.
P.I. James S. Economou, M.D., Ph.D.
Award time: 7/01/97-6/30/02.
NIH/NCI funding $1,022,040 total award.

K12 CA 76905: “Clinical Scientist Training in Cancer Gene Medicine”.
P.I. James S. Economou, M.D., Ph.D.
Award time:9/01/97-8/31/02.
NIH/NCI funding $1,404,720 total award.

Monkarsh Fund

Naify Fund

Stacy and Evelyn Kesselman Research Fund

The Leeb Fund

The Justice David Eagleson Fund

Richard Barasch Seed Grant Award: “Immunotherapy for Malignant Melanoma.”
Stop Cancer funding $30,000 total award.

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