PHILADELPHIA--Lymphocytes are known to infiltrate melanoma lesions at the primary site, occasionally resulting in spontaneous regressions. Therefore, investigators in search of specific treatments for metastatic melanoma have turned to immunologic approaches, John Kirkwood, MD, said at the 12th Annual Toward 2000 Symposium at Fox Chase Cancer Center.
PHILADELPHIA--Lymphocytes are known to infiltrate melanoma lesionsat the primary site, occasionally resulting in spontaneous regressions.Therefore, investigators in search of specific treatments formetastatic melanoma have turned to immunologic approaches, JohnKirkwood, MD, said at the 12th Annual Toward 2000 Symposium atFox Chase Cancer Center.
Some of Dr. Kirkwood's studies at the University of Pittsburgh'sMelanoma Center focus on antigens that elicit antibody responses,such as gangliosides on tumor cell surfaces. However, he said,the critical issue is whether a vaccine will elicit a T cell response,and in this regard peptide antigen vaccines appear to be goodcandidates.
Peptide antigens fall into two categories, Dr. Kirkwood said.Representative of the first are melan A or MART-1 (melanoma antigenrecognized by T cells) and tyrosinase, a pigmenting enzyme ofthe melanocyte lineage. These are lineage markers of melanomaand melanocytes, and are found in few other tissues.
The second category of peptide antigens is characterized by MAGE-1,MAGE-3, and other antigens that are cancer-associated and foundin no normal tissues except in the testis. These molecules areenfolded on the surface of tumor cells within HLA molecules.
Working with Dr. Kirkwood and Michael T. Lotze, MD, at the Universityof Pittsburgh, Walter Storkus, PhD, has been able to elute moleculesfrom the HLA and define a series of peptide antigens that arerecognized by T cells in association with specific HLA types.Since at least half of the population has tissue type HLA A2,the initial studies involve three peptides recognized by the immunecells of these patients: MART-1, gp100, and tyrosinase.
Patients are randomized to one of these peptides, and are immunizedonce weekly for 4 weeks with peptide combined with MF59, an oiladjuvant to increase immune response.
Dr. Kirkwood said that the trial is still accruing patients andhas not yet been unblinded, but already several patients haveshown mixed tumor regression.
Skin biopsies of these patients have revealed antigen-presentingLangerhans cells at the junction of the epidermis and dermis,as well as in the dermis. Also, the biopsy sites show activationand profound DR antigen expression.
In these early trials to induce immune responses, researchersare looking at safety issues, including the possible destructionof pigment-producing cells, such as in the skin and eyes. Suchdestruction may not be all bad, however, Dr. Kirkwood said, and,in fact, may be an indication that the therapy is working.
Since only about half the population has tissue type HLA A2, Dr.Kirkwood sees a need in the future for studies of a variety ofpeptide antigen vaccines that can be selected "off the shelf"according to the patient's HLA type.
He stressed that the peptide story is only the beginning of theimmunologic approach. He also foresees the need to test differentadjuvants, perhaps combining immunization with various cytokines,to enhance the response.