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Carcinoembryonic antigen (CEA), a tumor associated antigen expressed on many tumor types (including most colon cancers and over 50% of breast tumors), can be used as a target for the active immunotherapy of human cancer. While CEA alone is unable to elicit a strong anti-tumor response, laboratory studies have shown that when the gene for CEA is introduced into a vaccinia virus, the resulting construct can induce anti-CEA responses that can eliminate the tumor. This approach is being evaluated in a Phase I clnical study to determine whether a recombinant CEA-vaccinia virus construct can induce a specific imune respose to CEA-expressing human tumors. Similar constructs are being developed using the prostate specific antigen for the potential immunotherapy of human prostate cancer.
Prevention of Tumor Invasion and Metastasis
Exciting progress has been made in elucidating the genetic changes associated with tumor cell invasion and metastasis. Understanding the mechanism of action of these genetic changes has led to new strategies for therapy, diagnosis and prevention, some of which are currently being evaluated in clinical trials. CAI, a novel signal transduction inhibitor that blocks tumor cell cytokine-stimulated growth and motility, has been developed as a new cancer therapy approach which shows particular potential for ovarian and breast cancer. A clinical phase I trial for treatment of refractory cancers began in March 1992. Low toxicity and several promising tumor responses have been seen in the first 14 patients. CAI is also being developed as a potential chemopreventive agent. Significant progress has been made in our understanding of the NM23 family of genes in the regulation of tumor metastasis. Laboratory studies have revealed that expression of the human NM23 gene is reduced in highly metastatic human breast, hepatocellular and melanoma tumors, suggesting that NM23 may provide a new approach for predicting the agressiveness of an individula patint's tumor. Agents that modulate NM23 expression or function or that mimic its action may have therapeutic potential. TIMP-2, a protein that inhibits an enzyme responsible for the destruction of the basement membrane, has been shown in experimental studies to block tumor cell invasion and metastasis formation. The complete domain structure of TIMP-2 has been determined, and the chromosomal location of TIMP-2 on 17q has been determined and confirmed. Current data support the hypothesis that TIMP-2 may function as a tumor suppressor protein by inhibiting metalloproteinase activity required for invasion. In vivo TIMP-2 also arrests metastasis through inhibition of angiogenesis. Specific clinical applications of TIMP-2 could include the treatment of bone metastasis and Kaposi's sarcoma.
Development of a Human Papillomavirus Vaccine for Cervical Cancer
Studies over the past several years have established an etiological association for specific types of human papillomaviruses (HPV) and cervical cancer. Two HPV genes, L1 and L2, encode the proteins that form the viral coat of the virus, and thus they represent good candidates for an HPV vaccine. Preliminary studies using the closely related bovine papillomavirus have shown that, when expressed in insect cells, the L1 protein alone or the L1 and L2 proteins together self-assembled in the cells to form particles that can induce very high titers of neutralizing antibody. It is also possible to make particles from L1 or L1 plus L2 from HPV 16, the virus type that is associated most commonly with cervical cancers. In addition, a new laboratory assay based on HPV16 L1/L2 particles has been developed that can identify women infected with HPV. This assay, or a similar one based on a mixture of high risk HPV particles, may aid in determining the natural history of high risk HPV infection and might be useful as an adjunct to cervical cytologic screening to identify women at risk for developing cervical cancer.
Gamma Interferon
Gamma interferon was the first great hope for cytokine therapy of cancer. While this proved unrealistic, interferon is making a strong comeback as a critical regulator of immune responsiveness. It is believed to be one of the major control points in the lymphocyte-macrophage-NK cell communication pathway. The exact role of gamma interferon or any other cytokine in the immune system has not been determined because it is difficult to control the level of expression of a cytokine and because functional outcomes typically depend on cross-talk among many cytokines. Gene knockout technology has been very useful in sorting out cytokine function, and two groups have now provided complementary information about gamma interferon by preparing knockout mice lacking, respectively, expression of the interferon gene or the interferon receptor gene. The results are very similar. Mice lacking the receptor gene have increased susceptibility to infectious diseases. Their susceptibility to cancer has yet to be evaluated. A detailed study of macrophage function in these knockout mice has now shown that complete macrophage activation is impossible without gamma interferon. While gamma interferon has long been known to be a potent macrophage activating factor, other pathways of activation could be demonstrated in vitro. The recent results show that alternative pathways of macrophage activation are not physiologically relevant. This reemphasizes the importance of gamma interferon not only as a manipulator of macrophage function directly, but as a regulator of the balance between the helper T-cell subsets Th1 and Th2.
Tumor Angiogenesis
Continuing growth of a tumor absolutely depends on the simultaneous development of a vascular system to supply needed nutrients to the expanding cell population. The stimulus for the growth of this new vascular system apparently comes from the cancer itself as it reaches a distinct stage of cancer progression and switches on an angiogenic phenotype. Utilizing a unique tumor cell model where the timing of the conversion from non-angiogenic to angiogenic is highly predictable, a number of proteins have been identified which are associated with this phenotypic switch. Some of these proteins are well known growth factors with angiogenic activity, some are newly identified growth stimulating peptides. However, new proteins that are inhibitors of angiogenesis have also been discovered. As with many biological systems, angiogenesis seems to be regulated by inductive factors working in synergy and opposing the influence of inhibitors.
Innovative Techniques for the Identification of Genetic Alterations in Tumors
Comparative genomic hybridization (CGH) and arbitrarily primed polymerase chain reaction (AP-PCR) allow the entire genome of tumor cells to be scanned for disease related genetic alteration. No prior knowledge of the location of the alterations is needed. CGH is a novel application of fluorescence in situ hybridization (FISH), and AP-PCR amplifies genomic DNA sequences using sets of random PCR primers. These new techniques are being applied to the rapid identification of genetic alterations involved in cancer initiation and progression. AP-PCR was critical to the discovery of a unique alteration that is associated with some hereditary cases of colon cancer and characterized by widespread genomic instability. The development of recombinant toxins as anti-cancer agents represents an exciting new therapeutic approach to cancer and other diseases.
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