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Clinical Validation of Biomarkers

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  2. Clinical Validation of Biomarkers
  3. AIDS and Cancer
  4. Glioma DNA Vaccine

Xiao et al., pp. 2178–2186

Ideally, biomarkers should provide prognostic and diagnostic information about physiological disease states and disease progression. However, even in spite of recent technological advances, validating a new biomarker candidate is still a daunting task that hinges on the development of highly specific protein antibodies and their readily quantifiable detection.

To improve affinity biomarker validation in fixed patient tissue specimens, Xiao et al. developed a novel quantum dot-based imaging system based on chicken IgY antibodies. Chicken antibodies not only circumvent the cross-reactivity problems often encountered with mammalian antibodies but generally also display enhanced immunogenicity against conserved mammalian proteins due to the phylogenetic distance between humans and chickens.

The authors generated two new monospecific, polyclonal IgYs directed against two model cancer biomarker systems, HER2 and telomerase, and tested them for specificity by Western blot und immunohistochemistry on tumor and normal cells and for relative affinity by layered peptide array. The chicken antibodies outperformed commercially available mammalian antibodies for both HER2 and telomerase with regard to affinity and specificity. In tissue microarray experiments, HER2 quantitation correlated well with chromogenic in situ hybridization, whereas telomerase quantitation suggested a difference in telomerase values between tumors of Gleason Grade 6 and below and tumors of Gleason Grade 7 and above and between moderately and poorly differentiated tumors.

The combination of high-affinity chicken antibodies, novel quantum dot detection systems, complete fluorescence image capture using 3D-deconvolution microscopy and automated sample processing will facilitate clinical validation of novel biomarkers in large cohorts.

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Figure  . Representative deconvolution image processing lanes (top 4 panels) illustrated higher telomerase expressing cells (A-549, left stack) and very low expression cells (IMR90, right stack). After digital removal of unfocused light by deconvolution software, the total in-focus fluorescence is represented on the bottom grids.

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AIDS and Cancer

  1. Top of page
  2. Clinical Validation of Biomarkers
  3. AIDS and Cancer
  4. Glioma DNA Vaccine

Stein et al., pp. 2260–2265

Malignant tumors, particularly Kaposi's sarcoma, non-Hodgkin lymphoma and cervical cancer, have been common among AIDS patients since the disease was first recognized in 1981. All in all, at least 30% of people with AIDS in the developed world will develop cancer. Case-control studies in sub-Saharan Africa, however, have consistently shown lower risks of cancer development associated with HIV infection than in Western countries.

In this issue, Stein et al. report on 10 years of data (1995 – 2004) from an ongoing case control study to measure the association between infectious agents, including HIV, lifestyle factors and cancer, among the black patient population attending the 3 major tertiary hospitals in Johannesburg, 8,487 patients in total.

Taken together, in HIV-1-positive patients the risk of developing Kaposi's sarcoma was about 50-fold higher (OR = 47.1), 6-fold higher for developing non-Hodgkin's lymphoma (OR = 5.9), and about 1.5- to 2.5-fold higher for developing cervical (OR = 1.6), anogenital (OR = 2.2), squamous cell skin cancers (OR = 2.6), and Hodgkin's lymphoma (OR = 1.6). As observed previously in Africa, these risks are still about an order of magnitude lower than in developed countries. None of the other cancer types examined (lung, melanoma, oral, liver, stomach, leukemia and sarcomas) showed any significant increase in relation to HIV-1.

The development of HIV-related cancers has changed dramatically since the introduction of highly active antiretroviral therapy (HAART) into clinical practice. As HAART is slowly becoming available to public hospital patients in South Africa, cancer patterns will certainly start to change here as well.

Glioma DNA Vaccine

  1. Top of page
  2. Clinical Validation of Biomarkers
  3. AIDS and Cancer
  4. Glioma DNA Vaccine

Ueda et al., pp. 2274–2279

Growing brain tumors are difficult to treat and gliomas are no exception. Radiation and surgery hold the risk of damaging healthy brain tissue and not all chemotherapeutic drugs can cross the blood-brain barrier, making immunotherapy an attractive alternative treatment option.

For immunotherapy to be effective, the immune system must both identify the tumor as foreign and mount an effective response to destroy it. In an earlier study, Ueda et al. had identified a glioma antigen, SOX6, by serological screening of testis cDNA library sera from glioma patients; now they have examined whether a SOX6 DNA vaccine could induce SOX6-specific CTL responses to destroy brain tumors in vivo.

Following SOX6-DNA vaccination, CTLs specific for SOX6-positive glioma cells were induced, while normal self-cells that had expressed SOX6 earlier during embryogenesis appeared unharmed. The vaccine also exerted protective and therapeutic antitumor effects in glioma-bearing mice. Depletion of either CD8+ or CD4+ T-cell subsets abolished the protective immune response, suggesting that both cell populations are responsible for the antitumor activity of the SOX6-DNA vaccine.

Taken together, SOX6 might prove to be a useful target for a subset of gliomas after overcoming the low efficacy that many DNA vaccines share. Since DNA vaccines do not have the intrinsic ability to amplify and spread in vivo like some competent replication viral vaccine vectors do, their potency is limited.