Ebook Smith’s general urology (17/E): Part 2
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Ebook Smith’s general urology (17/E): Part 2
Immunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2ic antitumor immune response. This observation suggests tliat there are foreign proteins (antigens) on tumor cells tliat classically have been described as resulting in humoral and cellular immune responses. However, experimental models suggest chat a T-cell (cell-mediated) response may be more impo Ebook Smith’s general urology (17/E): Part 2rtant in the killing of tumor cells than a B-cell (humoral) response.A detailed description of the components of the immune system is beyond the scopeEbook Smith’s general urology (17/E): Part 2
of this chapter, but certain features of the immune system as the)’ pertain to diagnostic and therapeutic issues will be reviewed.Tumor AntigensTumorImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2permit the host to recognize a tumor as foreign. Tumor-Specific antigens have been shown to exist in oncogenesis models utilizing chemical, physical, and viral carcinogens but appear co be less common in models of spontaneous tumor development.The identification of tumor-specific antigens led to the Ebook Smith’s general urology (17/E): Part 2 theory' of immune surveillance, which suggests that the immune system is continuously trolling for foreign (tumorspecific) antigens. This theory' isEbook Smith’s general urology (17/E): Part 2
supported by the observation that at least some cancers are more common in immune-stippressed patients such as transplant patients or human immunodefiImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2which more closely resemble human carcinogenesis, appear to have a less extensive repertoire of tumor-specific antigens but instead have been found to express many rumor-associated antigens.Tumor-associated antigens are found on normal cells but either become less prevalent in normal tissue after em Ebook Smith’s general urology (17/E): Part 2bryogenesis (eg. alpha-fetoprotein [AFP]) or remain present on normal tissue but are overexpressed on cancer cells (eg, prostate-specific antigen [PSAEbook Smith’s general urology (17/E): Part 2
]). In either case, the more ubiquitous nature of these antigens appears to cause reduced immune reactivity (also known as tolerance)to the specific aImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2e required for T-cell stimulation).The development of monoclonal (hybridoma) technology has allowed rhe development of many antibodies against many tumor-associated antigens and has provided insight into the regulation and expression of these antigens. The reexpression or upregulation of these tumor Ebook Smith’s general urology (17/E): Part 2-associated antigens during carcinogenesis may lead to immune response (or loss of tolerance). Many novel therapeutic approaches have sought to breakEbook Smith’s general urology (17/E): Part 2
this tolerance, and approaches to enhance a patient’s immune response will be discussed.Humoral ImmunityA large number of monoclonal antibodies have bImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2nt markers in germ cell tumors. p-hCG is also expressed in a small percentage of patients with bladder carcinoma. Antibodies directed against specific targets such as vascular endothelial growth factor (vegF) have been correctly developed and are being tested for the treatment of both advanced prost Ebook Smith’s general urology (17/E): Part 2ate cancer ofRCC.Antibodies in Cancer Diagnosis& DetectionA. Prostate Cancer[mmunoassays are used to test both body fluids and tissues for the presencEbook Smith’s general urology (17/E): Part 2
e of tumor-associated antigens. In the urologic cancers, the most obvious example is the development of monoclonal antibodies against PSA. The utilityImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2tase, which has largely been replaced by PSA in screening programs and in patients with low tumor burden. Prostatic acid phosphatase may be of some use in detecting or following up bone297Copyright © 2008. 2004, 2001.2000 by The McGravz-Hill Companies, Inc. Click here for terms of use298 / CHAPTER 1 Ebook Smith’s general urology (17/E): Part 28metastases and as a predictive marker of response to therapy for metastatic disease, both hormone-sensitive and-insensirive. More recently, antibodieEbook Smith’s general urology (17/E): Part 2
s to prostate-specific membrane antigen (PSN-ĨA) have been used, primarily for immunohistochemistry.B. Renal Cell CarcinomaUnfortunately, there are asImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2 antigens are being evaluated.c. Bladder CancerTwo oncofetal antigens, P'hCG and carcinoembryonic antigen, are expressed by a minority (20% or less) of transitional cell carcinomas. These markers arc not routinely used, but in diagnostic dilemmas, measurement of scrum levels of (3-hCG or staining of Ebook Smith’s general urology (17/E): Part 2 tissue tor this antigen may be useful.D.Germ Cell TumorsAs described in Chapter 23, antibodies to hCG and AFP are routinely used to detect shed antigEbook Smith’s general urology (17/E): Part 2
en from germ cell tumors in the bloodstream. These antigens can also be detected on tissue samples in the setting of some diagnostic dilemmas. While tImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2 on tissue specimens, is pathognomic for a nonsemi-nomatous germ cell tumor, regardless of results of routine pathologic evaluation. In addition to their diagnostic utility, AFP and hCG can be used as markers of response to therapy and as predictive factors of outcome. For example, the international Ebook Smith’s general urology (17/E): Part 2 germ cell tumor risk classification schema tor patients with metastatic disease relics heavily on AFP and hCG levels as well as levels of a nonspecifEbook Smith’s general urology (17/E): Part 2
ic marker, lactate dehydrogenase, to assign patients with nonseminomatous germ cell tumors to 1 of 3 risk levels (see Chapter 23).E.RadioimmunodetectiImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2ited. Theoretically, such an approach could be used for the presurgical evaluation of disease, postsurgical evaluation for minimal residual disease, confirmation of cancer identified by other imaging modalities, and detection of recurrent disease. There arc several potential impediments to successfi Ebook Smith’s general urology (17/E): Part 2ll tumor radioimmunodetection. These include dilution of antibody in the bloodstream: metabolism of the antibody; nonspecific binding in liver, reticuEbook Smith’s general urology (17/E): Part 2
loendothelial system, bone marrow, and elsewhere: binding of antibody by circulating or shed antigen; and the development of neutralizing human ami-moImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2 antibody to PSMA. Its use has been hampered by a fairly laborious administration process, operator dependence in interpretation of scans, and a less than satisfactory positive predictive value. The use of11 In-capromab pendetide is described in Chapter 10.Immunotherapy with Monoclonal AntibodiesImm Ebook Smith’s general urology (17/E): Part 2unotherapy with monoclonal antibodies alone ("naked antibodies") has been fairly extensively evaluated. The use of monoclonal antibodies against tumorEbook Smith’s general urology (17/E): Part 2
-associated antigens has met with only limited success in patients with solid tumors. In lymphoproliferative disorders such as leukemia and lymphoma, Immunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2 but may in pan be mediated byresultant complement fixation.Direct antiproliferative effects of antibodies on cancer cells can be achieved by antibodies against functionally important antigens. Thus, the inhibition of growth factors and growth factor receptors and rhe activation or inhibition of sig Ebook Smith’s general urology (17/E): Part 2nal transducing molecules are attractive therapeutic targets. In die urologic cancers, while no approved monoclonal antibody therapy exists, trials ofEbook Smith’s general urology (17/E): Part 2
antibodies against growth factors, vascular endothelial growth factor (VEGF, an angiogenic molecule), and signal transduction molecules are being undImmunology & Immunotherapy of Urologic Cancers18Eric J. Small, MDBoth experimental and naturally occurring tumors arc capable of stimulating a specifi Ebook Smith’s general urology (17/E): Part 2ion in metastatic disease. Results from a trial of interferon-alpha with and without bevacizumab ate awaited. There is, as well, an ongoing trial of chemotherapy with and without bcvacizumab in patients with metastatic hormone refractory prostate cancer.An alternative approach to naked antibodies is Ebook Smith’s general urology (17/E): Part 2 to conjugate any of a variety of cytotoxic agents to an antibody. The advantage of this approach is a “bystander effect," making it unnecessary to usEbook Smith’s general urology (17/E): Part 2
e an antibody that binds each and every' cell. This can be achieved in a variety of ways. The most straightforward is to use the monoclonal antibody aGọi ngay
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