Immunotherapy of metastatic melanoma by reversal of immune suppression Page: 4 of 14
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The essential mechanism whereby cancer is prevented in man undoubtedly
involves the intracellular systems that identify significant genetic mutations and
activate apoptosis. The second line of defense is the extracellular systems that
identify cells with significant genetic mutations and effect cell destruction. NK-LAK
and cytotoxic T-cells function within this multifaceted system. These extracellular
systems are of particular interest in immunotherapy for they do not depend on
intracellular apoptosis systems which are obviously defective in cancer.
In general terms, cancer requires mutations that allow it to:
(1) Escape both intracellular and extracellular cell destruction when the
genome becomes abnormal.
(2) Escape extracellular and intracellular "control" signals to grow and not to
grow.
(3) Escape the need for adhesion molecules which define an "area code" in
order to replicate.
(4) Gain the ability to penetrate capillary epithelium and basement
membranes.
We believe one of the essential mutations allows the cancer to escape immune
surveillance and establish immune tolerance to tumor antigens. The mode of
expression of MHC class 2 molecules on the melanoma cell surface is part of that
tolerizing system.
The original proposal that the immune system functions to control cancer is
credited to Paul Ehrlich at the beginning of the 20th century. The modern
formulation of the hypothesis was presented by Burnett in 1967 (Ref 4). Whether or
not the immune system is of significant importance in determining the clinical
course of cancer is unsettled and has been debated for many years. Our
interpretation of the evidence is that it does operate in "early" cancer and that
immune surveillance is suppressed in advanced and metastatic cancer.
The etiology of melanoma is poorly defined. No specific carcinogenic chemicals and
no identified viruses have been implicated. The current belief is that melanoma is
the result of somatic mutations in the melanotic cells of the skin due to UV
exposure in "susceptible" individuals. Such mutated cells due to UV radiation
would be predictably antigenic. No melanoma specific antigens have been
identified; however, various melanoma associated antigens, primarily glycoproteins
and neuroglandular antigens, have been described. (Ref 5) Rosenberg and
coworkers (Ref 6) have identified a polypeptide epitope designated MART-1 27-35
which appears to be common to many different melanomas.
The presence of tumor infiltrating lymphocytes (TIL) is frequently found in the
histological slides in early melanoma and this has been interpreted as an immune
response against melanoma antigens. Indeed the presence of such TILs has been
January 1997
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Biggs, Max W. & Eiselein, John E. Immunotherapy of metastatic melanoma by reversal of immune suppression, report, January 1, 1997; California. (https://digital.library.unt.edu/ark:/67531/metadc681711/m1/4/: accessed April 18, 2024), University of North Texas Libraries, UNT Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.