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tumor-infiltrating lymphocytes (TILs) 721 tumor necrosis factor α (TNF-α)
TNF-α
TNF-α
TNF-β
SLe x
E-selectin
Tumor cell
SLe a
modifiers, monoclonal antibodies, cancer vaccines, and
gene therapy. Genetically engineered cytokines such as
interleukin-2 (IL2) and interferon-α (IFN-α) have been
used to activate the immune system. Early hopes for
success have now abated. Interferons have some proven
efficacy in the management of melanoma, renal cell carcinoma,
and hairy cell leukemia and as adjuvant therapy
in certain hematological malignancies such as low-grade
lymphoma and myeloma. Although IL2 has been used in
the past to treat renal cell carcinoma and melanoma with
the generation of tumor-infiltrating lymphocytes (TILs)
and lymphokine-activated killer (LAK) cells, it has toxic
physiologic effects. Monoclonal antibodies as anticancer
agents are promising but have problems with delivery to
targets and reactions to murine antibodies along with difficulties
in linking therapeutic war heads to these “smart
bombs.” Bispecific antibodies have been used to cross link
targets to immune effector cells to activate a cell-mediated
antitumor response. Current cancer vaccines include
autologous cell lines, allogeneic cell lines, genetically
modified tumor cells, glycoproteins, stripped glycoproteins,
peptides, antitumor idiotypes, and polynucleotides
encoding tumor antigens. Gene therapy may be used to
modify tumor cells to express costimulatory molecules
such as B7-1 to help initiate a cell-mediated response
against a neoplasm.
tumor-infiltrating lymphocytes (TILs)
Cytotoxic T lymphocytes within a tumor mass. T lymphocytes
isolated from the tumor they are infiltrating. They are
cultured with high concentrations of interleukin-2 (IL2),
leading to expansion of these activated T lymphocytes in
vitro. TILs are very effective in destroying tumor cells and
have proven much more effective than lymphokine-activating
killer (LAK) cells in experimental models; they have 50
to 100 times the antitumor activity produced by LAK cells.
TILs have been isolated and grown from multiple resected
human tumors, including those from kidney, breast, colon,
and melanoma. In contrast to the non-B/non-T LAK cells,
Inhibits tumor
cell proliferation
Tumor necrosis immunotherapy.
Cytolysis of
tumor cell
Vascular injury
Inhibits oxygen and blood
flow to the tumor
TILs nevertheless are generated from T lymphocytes and
phenotypically resemble cytotoxic T lymphocytes. TILs
from malignant melanoma exhibit specific cytolytic activity
against cells of the tumor from which they were extracted,
whereas LAK cells have a broad range of specificity. TILs
appear unable to lyse cells of melanomas from patients
other than those in whom the tumor originated. TILs may
be tagged so that they may be identified later.
tumor necrosis factor (TNF-)
A cytotoxic monokine produced by macrophages stimulated
with bacterial endotoxin. TNF-α participates in inflammation,
wound healing, and remodeling of tissue. TNF-α,
which is also called cachectin, can induce septic shock
and cachexia. It is a cytokine comprised of 157-amino acid
residues. It is produced by numerous types of cells including
monocytes, macrophages, T lymphocytes, B lymphocytes,
natural killer (NK) cells, and other types stimulated by
endotoxins or other microbial products. The genes encoding
TNF-α and TNF-β (lymphotoxin) are located on the short
arm of chromosome 6 in humans in the major histocompatibility
complex (MHC) region. High levels of TNF-α
are detectable in the blood circulation very soon following
administration of endotoxin or microorganisms. The
administration of recombinant TNF-α induces shock, organ
failure, and hemorrhagic necrosis of tissues in experimental
animals, including rodents, dogs, sheep, and rabbits, closely
resembling the effects of lethal endotoxemia. TNF-α is produced
during the first 3 days of wound healing. It facilitates
leukocyte recruitment, induces angiogenesis, and promotes
fibroblast proliferation. It can combine with receptors on
selected tumor cells and induce their lysis. TNF mediates
the antitumor action of murine natural cytotoxic (NC) cells
which distinguishes their functions from those of natural
killer (NK) and cytotoxic T cells. TNF-α was termed
cachectin because of its ability to induce wasting and anemia
when administered on a chronic basis to experimental
animals. Thus, it mimics the action in patients with cancer
and chronic infection with human immunodeficiency virus
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