Although
malignant mesothelioma is not a classically immunogenic
cancer, there is abundant evidence for immune recognition. The relative ease of obtaining
tumor tissue makes
mesothelioma ideal for studying surrogate
biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that
malignant mesothelioma patients as well as
asbestos-exposed persons without
mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several
biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by
interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells,
tumor necrosis factor-alpha (
TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-
tyrosine kinase (HSV-tk) followed by
ganciclovir, and immunomodulatory gene therapy with
IL-2,
IL-4,
interferon-gamma (IFN-gamma), IFN-alpha,
TNF-alpha,
granulocyte-macrophage colony-stimulating factor (
GM-CSF),
IL-6, and IL-1beta transfected into
tumors. Vaccinia virus has been studied as a vector for
cytokine gene transfer. Suicide gene therapy has been combined with a
tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in
malignant mesothelioma. Novel agents under study include the
angiogenesis inhibitors SU5416,
bevacizumab, and
thalidomide.
ZD1839, an orally administered, highly selective inhibitor of the
epidermal growth factor receptor (EGFR)
tyrosine kinase, is being tested in a phase II trial. Since
platelet-derived growth factor (PDGF) is thought to be an autocrine
growth factor for
mesothelioma STI-571 (
Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the
PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself.